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Depression and suicidal ideation have substantially increased among college students, yet many students with clinically significant symptoms do not perceive their distress as warranting mental health services. Personalized feedback (PF) interventions deliver objective data, often electronically, comparing an individual's reported symptoms or behaviors to a group norm. Several studies have shown promise for PF interventions in the context of mood and depression, yet little is known regarding how, and for whom, mood-focused PF interventions might be best deployed. The primary aim of this study was to examine the sociodemographic, clinical, and treatment-seeking factors associated with reviewing PF reports on emotional distress among college students (N = 1,673) screening positive for elevated suicide risk and not receiving mental health treatment. Results indicated that PF engagement was greatest among those with higher depression scores, and those reporting privacy/stigma concerns as barriers to treatment. Sexual minority students were more likely to review their PF than heterosexual students. Taken together, PF interventions may be a useful tool for engaging those with greater clinical acuity, and those hesitant to seek in-person care. Further research is warranted to examine the circumstances in which PF interventions might be used in isolation, or as part of a multitiered intervention strategy., (Copyright © 2021. Published by Elsevier Ltd.)

Genome-wide association studies of case-control status have advanced the understanding of the genetic basis of psychiatric disorders. Further progress may be gained by increasing sample size but also by new analysis strategies that advance the exploitation of existing data, especially for clinically important quantitative phenotypes. The functionally-informed efficient region-based test strategy (FIERS) introduced herein uses prior knowledge on biological function and dependence of genotypes within a powerful statistical framework with improved sensitivity and specificity for detecting consistent genetic effects across studies. As proof of concept, FIERS was used for the first genome-wide single nucleotide polymorphism (SNP)-based investigation on bipolar disorder (BD) that focuses on an important aspect of disease course, the functional outcome. FIERS identified a significantly associated locus on chromosome 15 (hg38: chr15:48965004 - 49464789 bp) with consistent effect strength between two independent studies (GAIN/TGen: European Americans, BOMA: Germans; n = 1592 BD patients in total). Protective and risk haplotypes were found on the most strongly associated SNPs. They contain a CTCF binding site (rs586758); CTCF sites are known to regulate sets of genes within a chromatin domain. The rs586758 - rs2086256 - rs1904317 haplotype is located in the promoter flanking region of the COPS2 gene, close to microRNA4716, and the EID1, SHC4, DTWD1 genes as plausible biological candidates. While implication with BD is novel, COPS2, EID1, and SHC4 are known to be relevant for neuronal differentiation and function and DTWD1 for psychopharmacological side effects. The test strategy FIERS that enabled this discovery is equally applicable for tag SNPs and sequence data., (Copyright © 2018 The Author(s). Published by Elsevier B.V. All rights reserved.)

There is growing evidence that inflammatory mediators play a critical role in the pathophysiology of both major depression and suicidal behavior. Immunological differences have been reported in both major affective disorders and suicidal behavior. Specifically, increased levels of pro-inflammatory cytokines have been shown to correlate with the severity of depression and various cytokines have been identified as potentially important in understanding the pathophysiology of major affective disorders/suicidality. We aimed to conduct a systematic review of the current literature to investigate the association between inflammatory cytokines and suicidal behavior. Only articles from peer-reviewed journals were selected for inclusion in the present review. Most studies documented the association between suicidality and IL2, IL-6, IL-8, TNF-α and VEGF levels that have been found altered in suicidal behavior. The presence of major depressive disorder (MDD) with suicidal ideation/attempts was associated with differences in inflammatory cytokine profile when compared to that without suicidal ideation/attempts. Most suicide attempters or subjects with suicidal ideation showed an imbalance of the immune system but this does not imply the existence of a causal link. Also, not all studies demonstrated a positive correlation between inflammatory cytokines and suicidal behavior. Further additional studies should elucidate the molecular mechanisms of the immune activation pathways underlying suicidality., (Copyright © 2013 Elsevier B.V. and ECNP. All rights reserved.)

Background: Recent genome-wide association studies have associated polymorphisms in the gene CACNA1C, which codes for Ca(v)1.2, with a bipolar disorder and depression diagnosis., Methods: The behaviors of wild-type and Cacna1c heterozygous mice of both sexes were evaluated in a number of tests. Based upon sex differences in our mouse data, we assessed a gene × sex interaction for diagnosis of mood disorders in human subjects. Data from the National Institute of Mental Health Genetics Initiative Bipolar Disorder Consortium and the Genetics of Recurrent Early-Onset Major Depression Consortium were examined using a combined dataset that included 2021 mood disorder cases (1223 female cases) and 1840 control subjects (837 female subjects)., Results: In both male and female mice, Cacna1c haploinsufficiency was associated with lower exploratory behavior, decreased response to amphetamine, and antidepressant-like behavior in the forced swim and tail suspension tests. Female, but not male, heterozygous mice displayed decreased risk-taking behavior or increased anxiety in multiple tests, greater attenuation of amphetamine-induced hyperlocomotion, decreased development of learned helplessness, and a decreased acoustic startle response, indicating a sex-specific role of Cacna1c. In humans, sex-specific genetic association was seen for two intronic single nucleotide polymorphisms, rs2370419 and rs2470411, in CACNA1C, with effects in female subjects (odds ratio = 1.64, 1.32) but not in male subjects (odds ratio = .82, .86). The interactions by sex were significant after correction for testing 190 single nucleotide polymorphisms (p = 1.4 × 10⁻⁴, 2.1 × 10⁻⁴; p(corrected) = .03, .04) and were consistent across two large datasets., Conclusions: Our preclinical results support a role for CACNA1C in mood disorder pathophysiology, and the combination of human genetic and preclinical data support an interaction between sex and genotype., (Copyright © 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: We have reported genetic linkage between bipolar disorder and markers on chromosome 6q16.3-22.1 in the National Institute of Mental Health Genetics Initiative wave 3 pedigrees. Here we test for: 1) robustness of the linkage to differing analysis methods, genotyping error, and gender-specific maps; 2) parent-of-origin effects; and 3) interaction with markers within the schizophrenia linkage region on chromosome 6p., Methods: Members of 245 families ascertained through a sibling pair affected with bipolar I or schizoaffective-bipolar disorder were genotyped with 18 markers spanning chromosome 6. Nonparametric linkage analysis was performed., Results: Linkage to 6q is robust to analysis method, gender-specific map differences, and genotyping error. The locus confers a 1.4-fold increased risk. Affected siblings share the maternal more often than the paternal chromosome (p =.006), which could reflect a maternal parent-of-origin effect. There is a positive correlation between family-specific linkage scores on 6q and those on 6p22.2 (r =.26; p <.0001). Linkage analysis for each locus conditioned on evidence of linkage to the other increases the evidence for linkage at both loci (p <.0005). Logarithm of the odds (LOD) scores increased from 2.26 to 5.42 on 6q and from.35 to 2.26 on 6p22.2., Conclusions: These results support linkage of bipolar disorder to 6q, uncover a maternal parent-of-origin effect, and demonstrate an interaction of this locus with one on chromosome 6p22.2, previously linked only to schizophrenia.

Objective: Studies on the course of major depressive disorder (MDD) among elderly persons are limited to short periods of follow-up, seldom provide comparisons with younger cohorts, and raise other methodological concerns., Methods: Utilizing 15 years of prospective data from the NIMH Collaborative Depression Study, the authors examined the index episode of MDD and the time until first observed recurrence in those who recovered for subjects in four age-groups defined by age at intake: 17-30, 31-50, 51-64, and 65-79 years. Assessments were conducted every 6 months for 5 years and annually thereafter. Survival analysis examined time until recovery and time to first recurrence., Results: Median time-to-recovery was similar for the four groups. Median time-to-first recurrence was significantly shorter for oldest versus the 51-64-year-old group but not the two other groups. The oldest age-group was distinguished from the younger groups by being more likely to be divorced/widowed/separated, to have primary depression, and to have a history of medical illness, particularly cardiovascular disease or cancer. There was no difference in the generally low levels of pharmacotherapy prescribed during the index episode or the subsequent well interval., Conclusions: Elderly patients with MDD may have a greater risk of recurrence than younger individuals. Low levels of treatment characterize the somatic treatment in all the study subjects, regardless of age-group.

Background: According to three earlier studies, well individuals with a family history of panic disorder experience more anxiety following a single breath of 35% CO(2) than do those without such a family history. This study sought to determine whether a heightened sensitivity to CO(2) manifests specifically in respiratory changes., Methods: Subjects were 18--35 years old and had no history of panic attacks and no current DSM-IV diagnosis other than simple or social phobia. Those at high risk for panic disorder (HR-P) (n = 46) had a first-degree relative with treated panic disorder. Low-risk control subjects (LR-C) (n = 39) had no first-degree relative with panic disorder. Respiratory measurements were taken continuously while subjects breathed room air through an attached mask for 3 min and, subsequently, while they breathed a 5% CO(2)/air mixture for an additional 3 min., Results: HR-P subjects did not differ from control subjects by group means of the principal measure of respiratory response, changes in minute volume (MV) during CO(2) inhalation. However, these values assumed clearly different distributions in the two groups. Fifteen (32.6%) of the HR-P subjects showed a paradoxical decrease in MV while breathing CO(2) and six (13%) displayed a particularly rapid increase in MV. Only one (2.6%) of the control subjects had a negative MV slope and none had a high value [chi(2)(1) = 12.3, p <.001, p =.021, Fisher exact test, respectively]. Though the subjects with high MV increases also described greater increases in anxiety after breathing CO(2), a regression analysis indicated that the MV increase was the more important in discriminating high-risk from control subjects., Conclusions: These results suggest that respiratory sensitivity to CO(2) inhalation is operative in the familial transmission of panic disorder.

Background: Studies of family history and lithium response in patients with bipolar affective disorder have produced mixed results, but the majority have shown relationships between the presence of affective disorder among relatives and positive responses to lithium in probands. The analysis presented here sought to confirm and to further characterize such relationships., Methods: Subjects described here participated in a long-term, prospective follow-up; had a history of Research Diagnostic Criteria manic disorder or schizoaffective disorder, manic type; and took lithium for periods of 26 weeks or longer. The majority participated in a family study in which first-degree relatives were directly interviewed. Morbidity during lithium and during anticonvulsant trials was quantified in alternative ways, as were the risks among first-degree relatives for bipolar I and nonbipolar affective disorders., Results: Familial loading for bipolar affective disorder was not associated with better outcomes during lithium treatment. Rather, the presence of major depressive disorder (MDD) among relatives was associated with slower improvement during acute treatment and with higher symptom levels during continuing treatment. Findings for morbidity during anticonvulsant treatment were similar. The patients who experienced symptom persistence with lithium did so as well during periods of anticonvulsant treatment and during periods without thymoleptics., Conclusions: A family history of MDD may have an enduring and negative prognostic significance that manifests across treatment conditions. Though difficult to reconcile with several earlier studies, these findings invite replication and further exploration.

The subjective response to a single-breath, 35% carbon dioxide challenge test shows promise as a tool for the study of panic disorder and may comprise a trait marker for that disorder. Little has been done to measure the reliability of test results, however. Subjects took a single breath at 35% CO2 and completed a self-rating of anxiety symptoms immediately thereafter. This procedure was repeated after a mean interval of 29 days. One group, considered at high risk for panic disorder, consisted of well, first-degree relatives of individuals treated for panic disorder. The control group included well subjects at high risk for affective disorder and subjects who had family histories negative for both affective disorder and panic disorder. On both testing occasions, subjects at high risk for panic disorder had symptom scores that were significantly higher than those of control subjects. Group differences in the portions who experienced a panic attack were dependent on the symptom threshold used to define an attack. A lower threshold was optimal with the second testing and a single, positive test result appeared to be more meaningful than a single negative result. The majority of individual symptom ratings were highly correlated across tests. Ratings for "smothering sensations," in particular, correlated highly across tests and consistently discriminated high-risk from control subjects. The sources of test result variability are unclear and warrant more investigation before the tests can be clinically useful. Research efforts should seek optimal thresholds to define positive test results within given data sets.

There is now substantial evidence that an abnormal threshold for suffocation alarm underlies panic disorder. Because this disorder is highly familial, evidence of an abnormal suffocation threshold may be apparent in high-risk individuals before they develop clinical illness. To explore this possibility, we used a single inhalation of 35% CO2 vs. air to evaluate 11 subjects who had at least one first-degree relative with DSM-III-R panic disorder, 13 who had at least two relatives treated for mania or for depression (HR-AD), and 15 low-risk controls who had no family history of panic disorder, affective disorder, or alcoholism (LR-C). All were aged 18-34 and had no history of panics or of any Research Diagnostic Criteria disorder. Five (45.5%) of the subjects at high risk for panic disorder, but none of the LR-C subjects (p = .007), nor any of the HR-AD subjects (p = .011), developed a panic attack following inhalation of the CO2 mixture.

Although the two disease concepts have very different histories, many previous studies have mixed conversion disorder and somatization disorder and none has made direct comparison between them. The authors applied DSM-III criteria to inpatient and outpatient medical records and attempted to follow 98 patients who met criteria for somatization disorder or conversion disorder. Five of these patients died 4 years later and, of those who survived, 70 (75.3%) were given follow-up interviews by a rater blind to baseline diagnosis. The 32 patients with a baseline diagnosis of conversion disorder were significantly less likely than the 38 patients with somatization disorder to be given the same diagnosis at follow-up. Six of the conversion disorder patients were given follow-up diagnoses of somatization disorder and, in four other cases, subsequent developments revealed medical explanations for the presenting complaint. Of the two baseline diagnoses, somatization disorder predicted substantially more impairment in a variety of domains.

In a large multicenter effort, major depressives were systematically studied at index admission and prospectively followed up for 5 years. Primary unipolar depressives with a family history of alcoholism (depression spectrum disease) differ from depressives with a family history of depression only (familial pure depressive disease) in having more familial anxiety and somatization disorder, more divorce, more suicide attempts, more negative life events, and needed more time to recover from the index episode. In the 5-year follow-up they are more likely to develop alcoholism and drug abuse. Depressive spectrum disease patients are more likely to meet systematic criteria for neurotic depression. The data suggest that major depression is a syndrome that is heterogeneous, and may be a final common pathway of more than one familial illnesses.

Seventy-seven patients with DSM-III panic disorder underwent a baseline dexamethasone suppression test (DST), participated in an 8-week controlled treatment trial, and provided follow-up interviews 2-4 years later. The 20 patients who had exhibited DST nonsuppression at baseline had more symptoms of anxiety, more work and social disability, and a greater likelihood of ongoing major depression than did patients who had had normal DST results. DST nonsuppression in panic disorder apparently indicates a more persistent and chronically disabling condition.

The authors used a naturalistic design to replicate studies which validated the familial subtyping of primary depression. Ninety-three inpatients with unipolar depression had received the DST within 1 week of admission and were free of confounding medical problems. A blind rater assigned diagnoses based on chart material recorded before DST results were known. The results supported the earlier conclusions of Schlesser et al. With 8 AM sampling, 53% of familial pure depressive disease patients and 14% of depression spectrum disease patients were nonsuppressors. Differences, though smaller, remained significant with multiple sampling. Only 1 of 24 patients with secondary depression had an abnormal DST. Patterns of nonsuppression among patients with psychotic features resembled those of the larger group.

We examined the association between post-dexamethasone suppression test (DST) serum cortisol and body weight, self-report of weight loss during the episode, and measured weight loss during the first week of admission in a series of 245 depressed inpatients. Data on measured weight loss between two successive admissions was available in a group of 57 depressed inpatients. Reported weight loss during the episode and measured weight loss during the first week of admission were not related to DST nonsuppression. In contrast, DST nonsuppression was significantly more frequent in patients with measured weight loss between two successive admissions. This association was particularly strong in patients with below-average body weight and was practically nonexistent in patients with above-average body weight. Multivariate analysis indicates that a significant association between DST results and weight loss may be missed if self-report is substituted for direct measurement of weight loss and if potential confounders, such as total body weight, age, and sex, are ignored.

Agoraphobic and panic disorder patients underwent 1-mg Dexamethasone Suppression Tests (DST) before, during, and after an 8-week trial of diazepam, alprazolam, or placebo. Previously described, never-ill controls underwent similar testing. At baseline, 21 of 82 (25.6%) panic disorder and 5 of 38 (13.2%) controls were nonsuppressors. This difference grew more marked with multiple testing over a 2-month period; 18 of 44 (40.9%) panic disorder patients were nonsuppressors on at least 1 of 3 tests compared with only 5 of 35 (14.3%) controls (p = 0.006). DST results were related to severity, but not to the presence or absence, of depressive syndromes. Control for plasma dexamethasone levels left highly significant differences in postdexamethasone cortisol across diagnostic groups. Neither DST results nor plasma dexamethasone levels changed in concert with clinical change, and type of treatment had little differential effect on these measures. Nor did DST results predict subsequent course when active treatment was extended by 6 months. However, DST results during the initial 8 weeks of treatment were strongly related to relapse when medications were tapered, even though this occurred 6 months after the last DST.

In an earlier report, the dexamethasone suppression test (DST) predicted globally rated outcome at discharge in 42 patients treated with ECT. To determine the predictive value of the DST following discharge we reevaluated these patients 6 months after admission. Suppressors and nonsuppressors did not differ in any of the follow-up measures; DST results added very little to the variance accounted for by diagnosis, age, and episode duration. Surprisingly, patients whose DST had converted at discharge from abnormal to normal were less likely to have sustained remission during follow-up than were patients whose DST had remained abnormal.

Some patients with panic disorder exhibit an abnormal response to dexamethasone. As this phenomenon may reflect disturbances in the central noradrenergic system and as alprazolam may work through this system to produce improvement, we predicted a particularly robust response among nonsuppressors. Fifty-two patients with panic disorder or with agoraphobia with panic attacks were given alprazolam as the sole treatment during either of 2, 8-week, double-blind, placebo-controlled trials. Though baseline clinical severity predicted globally rated outcome, baseline Dexamethasone Suppression Test results did not.