Decreased left amygdala functional connectivity by cognitive-coping therapy in obsessive-compulsive disorder.

It is of great clinical importance to explore more efficacious treatments for OCD. Recently, cognitive-coping therapy (CCT), mainly focusing on recognizing and coping with a fear of negative events, has been reported as an efficacious psychotherapy. However, the underlying neurophysiological mechanism remains unknown. This study of 79 OCD patients collected Yale-Brown Obsessive Compulsive Scale (Y-BOCS) and resting-state functional magnetic resonance imaging (rs-fMRI) scans before and after four weeks of CCT, pharmacotherapy plus CCT (pCCT), or pharmacotherapy. Amygdala seed-based functional connectivity (FC) analysis was performed. Compared post- to pretreatment, pCCT-treated patients showed decreased left amygdala (LA) FC with the right anterior cingulate gyrus (cluster 1) and with the left paracentral lobule/the parietal lobe (cluster 2), while CCT-treated patients showed decreased LA-FC with the left middle occipital gyrus/the left superior parietal/left inferior parietal (cluster 3). The z-values of LA-FC with the three clusters were significantly lower after pCCT or CCT than pretreatment in comparisons of covert vs. overt and of non-remission vs. remission patients, except the z-value of cluster 2 in covert OCD. CCT and pCCT significantly reduced the Y-BOCS score. The reduction in the Y-BOCS score was positively correlated with the z-value of cluster 1. Our findings demonstrate that both pCCT and CCT with large effect sizes lowered LA-FC, indicating that FCs were involved in OCD. Additionally, decreased LA-FC with the anterior cingulate cortex (ACC) or paracentral/parietal cortex may be a marker for pCCT response or a marker for distinguishing OCD subtypes. Decreased LA-FC with the parietal region may be a common pathway of pCCT and CCT. Trial registration: ChiCTR-IPC-15005969.

Effects of the COVID-19 Pandemic on Obsessive-Compulsive Symptoms Among University Students: Prospective Cohort Survey Study.

BACKGROUND: The COVID-19 pandemic is associated with common mental health problems. However, evidence for the association between fear of COVID-19 and obsessive-compulsive disorder (OCD) is limited. OBJECTIVE: This study aimed to examine if fear of negative events affects Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) scores in the context of a COVID-19-fear-invoking environment. METHODS: All participants were medical university students and voluntarily completed three surveys via smartphone or computer. Survey 1 was conducted on February 8, 2020, following a 2-week-long quarantine period without classes; survey 2 was conducted on March 25, 2020, when participants had been taking online courses for 2 weeks; and survey 3 was conducted on April 28, 2020, when no new cases had been reported for 2 weeks. The surveys comprised the Y-BOCS and the Zung Self-Rating Anxiety Scale (SAS); additional items included questions on demographics (age, gender, only child vs siblings, enrollment year, major), knowledge of COVID-19, and level of fear pertaining to COVID-19. RESULTS: In survey 1, 11.3% of participants (1519/13,478) scored ≥16 on the Y-BOCS (defined as possible OCD). In surveys 2 and 3, 3.6% (305/8162) and 3.5% (305/8511) of participants had scores indicative of possible OCD, respectively. The Y-BOCS score, anxiety level, quarantine level, and intensity of fear were significantly lower at surveys 2 and 3 than at survey 1 (P<.001 for all). Compared to those with a lower Y-BOCS score (<16), participants with possible OCD expressed greater intensity of fear and had higher SAS standard scores (P<.001). The regression linear analysis indicated that intensity of fear was positively correlated to the rate of possible OCD and the average total scores for the Y-BOCS in each survey (P<.001 for all). Multiple regressions showed that those with a higher intensity of fear, a higher anxiety level, of male gender, with sibling(s), and majoring in a nonmedicine discipline had a greater chance of having a higher Y-BOCS score in all surveys. These results were redemonstrated in the 5827 participants who completed both surveys 1 and 2 and in the 4006 participants who completed all three surveys. Furthermore, in matched participants, the Y-BOCS score was negatively correlated to changes in intensity of fear (r=0.74 for survey 2, P<.001; r=0.63 for survey 3, P=.006). CONCLUSIONS: Our findings indicate that fear of COVID-19 was associated with a greater Y-BOCS score, suggesting that an environment (COVID-19 pandemic) × psychology (fear and/or anxiety) interaction might be involved in OCD and that a fear of negative events might play a role in the etiology of OCD.

Genetic variation in human NPY expression affects stress response and emotion.

Understanding inter-individual differences in stress response requires the explanation of genetic influences at multiple phenotypic levels, including complex behaviours and the metabolic responses of brain regions to emotional stimuli. Neuropeptide Y (NPY) is anxiolytic and its release is induced by stress. NPY is abundantly expressed in regions of the limbic system that are implicated in arousal and in the assignment of emotional valences to stimuli and memories. Here we show that haplotype-driven NPY expression predicts brain responses to emotional and stress challenges and also inversely correlates with trait anxiety. NPY haplotypes predicted levels of NPY messenger RNA in post-mortem brain and lymphoblasts, and levels of plasma NPY. Lower haplotype-driven NPY expression predicted higher emotion-induced activation of the amygdala, as well as diminished resiliency as assessed by pain/stress-induced activations of endogenous opioid neurotransmission in various brain regions. A single nucleotide polymorphism (SNP rs16147) located in the promoter region alters NPY expression in vitro and seems to account for more than half of the variation in expression in vivo. These convergent findings are consistent with the function of NPY as an anxiolytic peptide and help to explain inter-individual variation in resiliency to stress, a risk factor for many diseases.

Association of 5-HTTLPR With Post-Traumatic Stress Disorder in US Service Members.

Objective: Post-traumatic stress disorder (PTSD) is a mental disorder that manifests after exposure to a stressful traumatic event, such as combat experience. Accumulated evidence indicates an important genetic influence in the development of PTSD. The serotonin transporter (5-HTT) gene has been identified as a candidate for PTSD and a polymorphism of the serotonin transporter-linked promoter region (5-HTTLPR) is associated with the disorder in the general population. However, whether it is associated with PTSD in active military service members has not been investigated. This study aimed to investigate the relationship between 5-HTTLPR and PTSD in service members. Methods: Leucocyte genomic DNA was extracted from service members, including those with PTSD (n = 134) or without PTSD (n = 639). The 5-HTTLPR polymorphism was detected by means of 2 stages of TaqMan fluorescent PCR assay. PTSD symptoms and symptom severity were assessed using the PTSD Checklist (PCL), a 17-item, DSM-based, self-report questionnaire with well-established validity and reliability. PTSD was determined based on endorsement of DSM-IV criteria and a PCL total score ≥ 44. Results: Significant differences in biallele distribution were observed between PTSD and controls (χ2 = 7.497, P = .024). The frequency of SS, SL, and LL genotypes in the PTSD group was 0.17, 0.56, and 0.27 respectively, compared to the frequencies of 0.27, 0.43, and 0.29 in non-PTSD controls. Carriers of the L allele had higher scores for reexperiencing and arousal symptoms on the PCL, compared to SS homozygote carriers (P < .05). The triallele genotypes showed no significant differences in distribution between the PTSD and control groups (P > .05) and no relationship with PTSD symptom severity. The interaction of triallelic genotypes of 5-HTTLPR and traumatic life events was associated with re-experiencing, avoidance, and arousal (P < .05 for all). Multiple regression analysis revealed significant correlations between both biallelic and triallelic genotypes of 5-HTTLPR, the interaction of the number of stressful lifetime events, and 5-HTTLPR genotypes with PCL total score (P < .001). Conclusion: Our findings suggested that 5-HTT might play a minor role in PTSD, and the interaction between 5-HTTLPR and the environment had effects on PCL score, complementing and emphasizing 5-HTT for PTSD, especially in the military population.

Sex-related difference of association of mitochondrial DNA copy number with PTSD in U.S. service members.

Gender differences in the lifetime prevalence of post-traumatic stress disorder (PTSD) have been well described with rates reported as approximately 10%-12% in females and 5%-6% in males (Olff, 2017). This study examined whether the sex-related difference of mitochondrial DNA copy number (mtDNAcn), an emerging systemic index of mitochondrial biogenesis and function can serve as a potential biomarker for PTSD. Leukocyte mtDNAcn of service members with PTSD (male = 127, female = 24) or without PTSD (male = 621, female = 78) was assessed using a TaqMan assay. The results were validated by the absolute quantification of QX-200 droplet digital PCR (ddPCR). PTSD symptoms and symptom severity were assessed using the PTSD Checklist (PCL), a 17-item, DSM-based, self-report questionnaire with well-established validity and reliability. DSM-IV criteria and PTSD were determined by PCL total score. We found that mtDNAcn of female subjects with PTSD was significantly higher compared to either male or female non-PTSD controls or male subjects with PTSD (p < 0.05). There was no significant difference in mtDNAcn between males with PTSD and male/female controls without PTSD. Using in vitro cultured SH-SY5Y cells (human neuroblastoma), we demonstrated that estrogen (Estro) treatment significantly decreased mtDNAcn (P < 0.001) compared to the vehicle control. We also found that pre-treatment with either synthetic glucocorticoid dexamethasone (Dex) or Estro blocker tamoxifen (Tamox) attenuated the estrogen-induced decreases of mtDNAcn. Our data suggest that mtDNAcn may be gender-dependent in the Servicemembers with PTSD. Glucocorticoid and/or estrogen receptors may play a role in the regulation of mtDNAcn. The sex-related difference of mtDNAcn may serve as a PTSD biomarker for females.

Left Amygdala Functional Connectivity Decreased after Fear of Negative Events was Disregarded in Obsessive-Compulsive Disorder.

Obsessive-compulsive disorder (OCD) is a chronic and debilitating mental disorder that affects patients throughout their lives, leading to a diminished quality of life for patients and families, reduced productivity, and higher health care costs. It is of clinical and theoretical importance to investigate a more efficacious therapeutic approach for OCD and the neurophysiological mechanism underlying the efficacy of treatment, potentially associated with the etiology of OCD. Recently, a novel psychotherapy designated cognitive-coping therapy (CCT) has been reported to have a large effect size in OCD treatment. CCT hypothesizes that fear of negative events plays a crucial role in OCD. The study entitled "Decreased left amygdala functional connectivity by cognitive-coping therapy in obsessive-compulsive disorder" attempted to investigate the potential neurophysiological mechanism underlying the efficacy of CCT for OCD. The study provides crystal evidence showing that 4-week pharmacotherapy plus CCT decreases the left amygdala seed-based functional connectivity (LA-FC) with the right anterior cingulate gyrus and the left paracentral lobule/the left superior parietal/left inferior parietal, and 4-week CCT decreases the LA-FC with the left middle occipital gyrus/the left superior parietal. The alteration of the LA-FC with the right anterior cingulate gyrus positively correlates to the reduction of the Yale-Brown obsessive-compulsive scale (Y-BOCS) score. Therefore, it provides new insights into understanding the neurophysiology and neuropsychology behind the onset and treatment of OCD.

Effects of short-term cognitive-coping therapy on resting-state brain function in obsessive-compulsive disorder.

BACKGROUND: Obsessive-compulsive disorder (OCD) tends to be treatment refractory. Recently, cognitive-coping therapy (CCT) for OCD is reported to be an efficacious psychotherapy. However, the underlying neurophysiological mechanism remains unknown. Here, the effects of CCT on OCD and the resting-state brain function were investigated. METHODS: Fifty-nine OCD patients underwent CCT, pharmacotherapy plus CCT (pCCT), or pharmacotherapy. Before and after a 4-week treatment, Yale-Brown obsessive-compulsive scale (Y-BOCS) was evaluated and resting-state functional magnetic resonance imaging (rs-fMRI) was scanned. RESULTS: Compared with the baseline, significant reduction of Y-BOCS scores was found after four-week treatment (p < .001) in groups of CCT and pCCT, not in pharmacotherapy. Post-treatment Y-BOCS scores of CCT group and pCCT group were not different, but significantly lower than that of pharmacotherapy group (p < .001). Compared with pretreatment, two clusters of brain regions with significant change in amplitude of low-frequency fluctuation (ALFF) were obtained in those who treated with CCT and pCCT, but not in those who received pharmacotherapy. The ALFF in cluster 1 (insula, putamen, and postcentral gyrus in left cerebrum) was decreased, while the ALFF in cluster 2 (occipital medial gyrus, occipital inferior gyrus, and lingual gyrus in right hemisphere) was increased after treatment (corrected p < .05). The changes of ALFF were correlated with the reduction of Y-BOCS score and were greater in remission than in nonremission. The reduction of the fear of negative events was correlated to the changes of ALFF of clusters and the reduction of Y-BOCS score. CONCLUSIONS: The effectiveness of CCT for OCD was related to the alteration of resting-state brain function-the brain plasticity. TRIAL REGISTRATION: ChiCTR-IPC-15005969.

Potential chemokine biomarkers associated with PTSD onset, risk and resilience as well as stress responses in US military service members.

Cytokines, including chemokines, are small secreted proteins, which specifically effect on the interactions and communications between cells. Pro-inflammatory cytokines are produced predominantly by activated macrophages and are involved in the upregulation of inflammatory reactions. Dysregulation of cytokines is associated with post-traumatic stress disorder (PTSD). Here, we use both before-and-after and case-control studies to search for potential chemokine biomarkers associated with PTSD onset, risk, and resilience as well as stress responses in US military service members deployed to Iraq and Afghanistan. Blood samples and scores of the PTSD Checklist (PCL) were obtained from soldiers pre- and post deployment (pre, post). Forty chemokines were measured using the Bio-Plex Pro Human Chemokine Panel Assays. The before-and-after analysis showed potential markers (CCL2, CCL15, CCL22, CCL25, CXCL2, and CXCL12) are associated with PTSD onset, and CCL3, CXCL11, and CXCL16 are related to stress response. The case-control study demonstrated that CCL13, CCL20, and CXCL6 were possible PTSD risk markers, and CX3CL1 might be a resilience marker. In addition, CCL11, CCL13, CCL20, and CCL25 were correlated with the PCL scores, indicating their association with PTSD symptom severity. Our data, for the first time, suggest that these dysregulated chemokines may serve as biomarkers for PTSD onset, risk, and resilience as well as stress responses, and may benefit developing approaches not only for PTSD diagnosis but also for PTSD treatment.

Clinical remission of a treatment-refractory individual with severe repetitive rituals and rumination.

BACKGROUND: Obsessive-compulsive disorder (OCD) is a severe chronic mental disorder and tends to be refractory to pharmacotherapy or psychotherapy. For treatment-refractory patients, neurosurgical interventions are options. 64 % of OCD patients who undergo neurosurgery still have greater than 16 in the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) after a long-term follow-up. Here, we reported a patient living with long-term OCD (20 years) who was refractory to pharmacotherapy, mindfulness-based psychotherapy, and neurosurgery that injured his bilateral anterior cingulates (AC) and caudate nucleus. METHODS: The patient accepted a novel psychotherapy named cognitive-coping therapy (CCT) and completed Y-BOCS, Hamilton depression rating scale, the Hamilton anxiety rating scale, social and occupational function assessment, and resting-state function magnetic resonance imaging scans (rs-fMRI) before and after 4-week CCT. RESULTS: His Y-BOCS score was reduced from 25 to 4. His depression score and anxiety score were reduced from 19 to 3 and from 12 to 3, respectively. The global assessment of functioning score increased from 32 to 88. CONCLUSIONS: The remission of the patient suggested that CCT could be an alternative intervention for treatment-refractory OCD and those with severe OCD could be cured in short-term.

Genetic association of FKBP5 with PTSD in US service members deployed to Iraq and Afghanistan.

Post-traumatic stress disorder (PTSD) is a debilitating mental disorder with a prevalence of more than 7% in the US population and 12% in the military. An interaction of childhood trauma with FKBP5 (a glucocorticoid-regulated immunophilin) has been reported to be associated with PTSD in the general population. However, there are few reports on the association of FKBP5 with PTSD, particularly in important high-risk population such as the military. Here, we examined the association between four single-nucleotide polymorphisms (SNPs; rs3800373, rs9296158, rs1360780, rs9470080) covering the FKBP5 gene and probable PTSD in US service members deployed to Iraq and Afghanistan, a high-risk military population (n = 3890) (Hines et al., 2014). We found that probable PTSD subjects were significantly more likely to carry the A-allele of rs3800373, G-allele of rs9296158, C-allele of rs1360780, and C-allele of rs9470080. Furthermore, the four SNPs were in one block of strong pairwise linkage disequilibrium (r = 0.91-0.96). Within the block there were two major haplotypes of CATT and AGCC (rs3800373-rs9296158-rs1360780-rs9470080) that account for 99% of haplotype diversity. The distribution of the AGCC haplotype was significantly higher in probable PTSD subjects compared to non-PTSD (p<.05). The diplotype-based analysis indicated that the AGCC carriers tended to be probable PTSD. In this study, we demonstrated the association between FKBP5 and probable PTSD in US service members deployed to Iraq and Afghanistan, indicating that FKBP5 might be a risk factor for PTSD.

BHLHB2 controls Bdnf promoter 4 activity and neuronal excitability.

Brain-derived neurotrophic factor (BDNF), via activation of TrkB receptors, mediates vital physiological functions in the brain, ranging from neuronal survival to synaptic plasticity, and has been implicated in the pathophysiology of neurodegenerative disorders. Although transcriptional regulation of the BDNF gene (Bdnf) has been extensively studied, much remains to be understood. We discovered a sequence within Bdnf promoter 4 that binds the basic helix-loop-helix protein BHLHB2 and is a target for BHLHB2-mediated transcriptional repression. NMDA receptor activation de-repressed promoter 4-mediated transcription and correlated with reduced occupancy of the promoter by BHLHB2 in cultured hippocampal neurons. Bhlhb2 gene -/- mice showed increased hippocampal exon 4-specific Bdnf mRNA levels compared with +/+ littermates under basal and activity-dependent conditions. Bhlhb2 knock-out mice also showed increased status epilepticus susceptibility, suggesting that BHLHB2 alters neuronal excitability. Together, these results support a role for BHLHB2 as a new modulator of Bdnf transcription and neuronal excitability.

Dynamic chromatin remodeling events in hippocampal neurons are associated with NMDA receptor-mediated activation of Bdnf gene promoter 1.

To determine the epigenetic events associated with NMDA receptor-mediated activation of brain-derived neurotrophic factor gene (Bdnf) promoter 1 by hippocampal neurons in culture, we screened 12 loci across 4.5 kb of genomic DNA 5' of the transcription start site (TSS) of rat Bdnf for specific changes in histone modification and transcription factor binding following NMDA receptor stimulation. Chromatin immunoprecipitation (ChIP) assays showed that NMDA receptor stimulation produced a durable, time-dependent decrease in histone H3 at lysine 9 dimethylation (H3K9me2), within 3 h after NMDA treatment across multiple loci. Concomitant increases in H3K4me2 and H3K9/14 acetylation (H3AcK9/14) were associated with transcriptional activation, but occurred at fewer sites within the promoter. The decrease in H3K9me2 was associated with release of HDAC1, MBD1, MeCP2, and REST from specific locations within promoter 1, although with different kinetics. In addition, occupancy of sites proximal to and distal to the TSS by the transcription factors NF-kappaB, CREB-binding protein (CBP), and cAMP-response element-binding protein were correlated with increased occupancy of RNA polymerase II at two loci proximal to the TSS following NMDA receptor stimulation. These temporal changes in promoter occupancy could occur thousands of base pairs 5' of the TSS, suggesting a mechanism that produces waves of Bdnf transcription.

Updates in PTSD Animal Models Characterization.

Post-traumatic stress disorder (PTSD) is a chronic, debilitating mental disorder afflicting more than 7% of the US population and 12% of military service members. Since the Afghanistan and Iraq wars, thousands of US service members have returned home with PTSD. Despite recent progress, the molecular mechanisms underlying the pathology of PTSD are poorly understood. To promote research on PTSD (especially its molecular mechanisms) and to set a molecular basis for discovering novel medications for this disorder, well-validated animal models are needed. However, to develop PTSD animal models is a challenging process, due to predisposing factors such as physiological, behavioral, emotional, and cognitive changes that emerge after trauma. Currently, there is no well-validated animal model of PTSD, although several stress paradigms mimic the behavioral symptoms and neurological alterations seen in PTSD. In this chapter, we will provide an overview of animal models of PTSD including learned helplessness, footshock, restraint stress, inescapable tail shock, single-prolonged stress, underwater trauma, social isolation, social defeat, early-life stress, and predator-based stress. We emphasize rodent models because they reproduce some of the behavioral and biotical phenotypes seen in PTSD. We will also present data showing that homologous biological measures are increasingly incorporated in studies to assess markers of risk and therapeutic response in these models. Therefore, PTSD animal models may be refined in hopes of capitalizing on the understanding of the molecular mechanisms and delivering tools in order to develop new and more efficacious treatments for PTSD.

Genetic predictor of current suicidal ideation in US service members deployed to Iraq and Afghanistan.

OBJECTIVE: Suicide is one of the ten leading causes of death in United States and the suicide rate in the military population has increased since the start of the Iraq and Afghanistan wars. However, few biomarkers for current suicidal ideation (CSI) have been identified. The current study examined the association of four candidate genes with CSI in active duty US Army Special Operations Command and National Guard units (n = 3,889) who served in Iraq and Afghanistan between November 2009 and July 2014. METHODS: Current PTSD symptoms and CSI were assessed using the PTSD Checklist (PCL) and PHQ-9, respectively. Traumatic events were assessed using items from the Life Events Checklist (LEC) that met the DSM-IV PTSD criteria of a traumatic stressor. All genotypes of saliva DNA were discriminated using the TaqMan 5'-exonuclease assay. RESULTS: The associations between CSI and brain-derived neurotrophic factor (BDNF), FK506 binding protein (FKBP5), catechol-O-methyltransferase (COMT), or S100A10 (p11) were examined. We found CSI was associated with BDNF (OR = 1.5, 95% CI = 1.5-1.8, P = 0.0002), but not FKBP5, COMT and p11. Female soldiers reported CSI more often than males (χ2 = 7.403, p = 0.0065), although gender did not affect CSI severity. In addition, associations were found between CSI and depression, PTSD, and BDNF, but not traumatic events. The BDNF Val66Met contributed to the severity of CSI even after adjusting to PTSD, depression and LEC. CONCLUSIONS: The associations of BDNF with CSI and its severity suggest that BDNF may be a predictor of suicidal risk and present an opportunity to develop laboratory tools with clinical implications in suicide prevention and treatment.

Association between leukocyte telomere length and hostility in US army service members.

Hostility is a common form of emotionally charged anger which can lead to maladaptive and unhealthy behaviors. Significant association between shortened telomeres and greater levels of hostility has been observed in civilian populations, but has not yet been comprehensively studied in military populations. Our study investigates the relationship between hostility, post-traumatic stress disorder (PTSD), and leukocyte telomere length (LTL) in a sample of United States Army Special Operations personnel (n = 474) who deployed to Iraq and/or Afghanistan as part of combat operations. Hostility was measured with five items from the Brief Symptom Inventory (BSI). PTSD was determined using the PTSD Checklist (PCL) total score. The LTL was assessed using quantitative polymerase chain reaction methods and regression analyses were conducted to determine the association of hostility and telomere length. PTSD subjects reported higher hostility scores compared with those without PTSD. Among the participants with PTSD, those with medium or high level of hostility had shorter LTL than those with low level hostility (P < 0.01). Stepwise regression indicated that hostility level and age, but not gender and PTSD, were negatively correlated with LTL. Univariate regression showed that total hostility score was negatively associated with LTL (CI= -0.06 to -0.002, Beta= -0.095, p < 0.039) as well as a significant correlation between LTL and hostility impulses (HI) (CI= -0.108 to -0.009, Beta= -0.106, p < 0.021) and hostility controlling (HC) (CI= -0.071 to -0.002, Beta= -0.095, p < 0.004). Multiple regression analyses revealed that, while HC has no significant association with LTL, HI was still negatively correlated with LTL (p = 0.021). Our data indicates that LTL is associated with HI levels. Prevention and treatment efforts designed to reduce hostility may help mitigate risk for LTL shortening, a process of cellular aging, and thus slow accelerated aged-related health outcomes.

Association between a functional serotonin transporter promoter polymorphism and citalopram treatment in adult outpatients with major depression.

CONTEXT: The HTTLPR, a functional polymorphism of the serotonin transporter gene solute carrier family 6 (neurotransmitter transporter, serotonin), member 4 (SLC6A4), promoter, affects transcription and may be involved in antidepressant drug treatment outcome, although response rates with antidepressants can be lower in patients who experience adverse effects. OBJECTIVE: To test the hypothesis that HTTLPR is associated with treatment outcome to citalopram. DESIGN: A clinical effectiveness trial, Sequenced Treatment Alternatives to Relieve Depression, collected DNA samples from outpatients with nonpsychotic major depressive disorder who received citalopram in the first treatment step. The triallelic HTTLPR locus was genotyped in 1775 samples to discriminate between long (L) and short (S) alleles, followed by the A > G substitution. The low-expression S and L(G) alleles were grouped together compared with the high-expression L(A) allele. SETTING: Eighteen primary care and 23 psychiatric care sites across the United States. PARTICIPANTS: Ages 18 to 75 years, meeting criteria for single or recurrent nonpsychotic major depression. MAIN OUTCOME MEASURES: Categorical response, remission, tolerance, and adverse effect burden. RESULTS: Expression-based grouping produced a significant finding of association between the L(A) allele and adverse effect burden in the entire sample (P = .004 [genotype frequency]; P < .001 [allele frequency]). To control for bias from population stratification, a white American subsample was analyzed. A lesser adverse effect burden was associated with L(A)L(A) genotype frequency (P = .03) or L(A) allele frequency (P = .007). These findings in white patients did not hold when the L allele was undifferentiated. No association was observed between treatment outcome phenotypes and HTTLPR. Development of diarrhea and the presence of the low-expression S or L(G) alleles were the strongest risk factors associated with adverse effect burden. CONCLUSIONS: The HTTLPR polymorphism is associated with citalopram adverse effects. Because the L(A) allele confers increased SLC6A4 transcription, increased serotonin transporter levels in brain and other tissues may lead to fewer adverse effects for antidepressant medications that target the transporter.

Brain serotonin transporter binding in depressed patients with bipolar disorder using positron emission tomography.

CONTEXT: Depression in bipolar disorder is clinically indistinguishable from that observed in major depressive disorder. As in major depression, selective serotonin reuptake inhibitors targeting brain serotonin transporters are first-line treatments for bipolar depression. Associations of serotonin transporter promoter polymorphisms and bipolarity have been reported; however, research on alterations in serotonergic neurotransmission in bipolar depression remains scant. OBJECTIVES: To assess in vivo brain serotonin transporter binding potential (BP(1), proportional to serotonin transporter number) in patients with bipolar depression and controls and to examine the relationship between serotonin transporter binding and genotype. DESIGN: Case-control study. SETTING: University hospital. PARTICIPANTS: A sample of 18 medication-free patients with bipolar depression and 41 controls. MAIN OUTCOME MEASURES: In vivo brain serotonin transporter binding was measured using positron emission tomography and radiolabeled trans-1,2,3,5,6,10-beta-hexahydro-6-[4-(methylthio)phenyl]pyrrolo-[2,1-a]-isoquinoline ([(11)C](+)-McNeil 5652). Participants were genotyped assessing biallelic and triallelic 5-HTTLPR polymorphisms. RESULTS: Patients with bipolar disorder had 16% to 26% lower serotonin transporter BP(1) in the midbrain, amygdala, hippocampus, thalamus, putamen, and anterior cingulate cortex. Triallelic 5-HTTLPR genotypes were unrelated to serotonin transporter BP(1). CONCLUSIONS: Lower serotonin transporter BP(1) in bipolar depression overlaps with that observed in major depression and suggests that serotonergic dysfunction is common to depressive conditions.

Duration of untreated psychosis (DUP) and outcome of people with schizophrenia in rural China: 14-year follow-up study.

This study aims to examine the relationship between the duration of untreated psychosis (DUP) and 14-year outcomes of schizophrenia in a Chinese rural area. Participants with schizophrenia (n = 510) were identified in an epidemiological investigation of 123 572 people aged 15 years and older in 1994 and followed up in 2008 in Xinjin, Chengdu, China. Longer DUP (>6 months) was common in participants (27.3%). In 1994, participants with DUP ≤ 6 months were more likely to have a significantly lower rate of suicide attempts, shorter duration of illness and higher rate of full remission compared with those with DUP > 6 months. No significant differences were found regarding the rates of survival, suicide, death due to other causes and homelessness between individuals with shorter and longer DUP in 2008. Nevertheless, longer DUP (>6 months) of participants in 2008 was significantly associated with higher mean of PANSS total negative and general mental scores, longer duration of illness and higher rate of live alone in the logistic regression model. Earlier identification, treatment and rehabilitation, and family intervention should be addressed when developing mental health policies and delivering community mental health services.

Interaction between childhood trauma and serotonin transporter gene variation in suicide.

Although the serotonin transporter promoter polymorphism (5-HTTLPR) contributes to depression and suicidality in a fashion modulated by environmental stress, 5-HTTLPR has been little examined in relation to suicidal behavior in substance dependence. Recently, a third functional allele of 5-HTTLPR was discovered enabling more of the interindividual variation in serotonin transporter expression to be predicted by genotype. We examined whether the 5-HTTLPR gene alone, or interacting with childhood trauma, was predictive of suicidal behavior in substance-dependent patients, a clinical population that is at high risk of suicide, as well as childhood trauma and other stress. We interviewed 306 abstinent male African-American substance-dependent patients about whether they had ever attempted suicide and administered the 34-item Childhood Trauma Questionnaire (CTQ). Patients and 132 male African-American controls were genotyped to determine the S, L(G), and L(A) 5-HTTLPR alleles; some analyses grouped the S and L(G) alleles on the basis of equivalent function. The distribution of 5-HTTLPR genotypes did not differ between patients and controls, nor between suicide attempters and non-attempters. However, patients with low expression 5-HTTLPR genotypes and above-median CTQ scores were more likely to have attempted suicide. Logistic regression showed increasing risk of a suicide attempt with increasing reports of childhood trauma scores; in addition, this increase was exaggerated among those with low expression forms of the 5-HTTLPR genotype. Childhood trauma interacts with low expressing 5-HTTLPR genotypes to increase the risk of suicidal behavior among patients with substance dependence.

Differential effects of 5-HTTLPR genotypes on the behavioral and neural responses to tryptophan depletion in patients with major depression and controls.

CONTEXT: Tryptophan depletion (TD) is a model used to study the contribution of reduced serotonin transmission to the pathogenesis of major depressive disorder (MDD). Recent studies have not sufficiently addressed the relative contribution of a functional-length triallelic polymorphism in the promoter of the serotonin transporter, 5-HTTLPR, to the behavioral and neural responses to TD in individuals with remitted MDD (rMDD) and controls. OBJECTIVE: To determine the role of 5-HTTLPR on the behavioral and neural responses to TD in medication-free patients with rMDD and individually matched controls. DESIGN: Participants were stratified according to diagnosis and 5-HTTLPR genotypes and underwent TD on one test day and sham depletion on the other test day in a prospective, double-blind, randomized order. SETTING: Outpatient clinic. PARTICIPANTS: Twenty-seven medication-free patients with rMDD (18 women and 9 men) and 26 controls (17 women and 9 men). INTERVENTIONS: Tryptophan depletion was induced by administration of capsules containing an amino acid mixture without tryptophan. Sham depletion used identical capsules containing lactose. Fludeoxyglucose F 18 positron emission tomography was performed 6 hours after TD. Magnetic resonance images were obtained for each participant. MAIN OUTCOME MEASURES: Quantitative positron emission tomography of regional cerebral metabolic rates for glucose and measures of depression using the Hamilton Depression Rating Scale. RESULTS: Behavioral responses to TD are affected by 5-HTTLPR in patients with rMDD and controls. A direct effect of 5-HTTLPR on the regulation of regional cerebral metabolic rates for glucose was identified in patients with rMDD for the amygdala, hippocampus, and subgenual anterior cingulate cortex. CONCLUSIONS: Variations in 5-HTTLPR modulate the sensitivity of patients with rMDD and controls to the behavioral effects of TD. In patients with rMDD, variations in triallelic 5-HTTLPR have a direct effect on regulation of regional cerebral metabolic rates for glucose in a corticolimbic circuit that has been implicated in rMDD.