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Importance: Increasing evidence suggests a potential role of immune-modulatory drugs for treatment-resistant depression. This scoping review explores the emerging evidence regarding the antidepressant effects of monoclonal antibodies (mAbs), a relatively newer class of immune therapeutics with favorable safety profile., Observations: PubMed was searched up to November 2023 for English publications addressing the antidepressant effects of mAbs, including meta-analyses, randomized controlled trials, open-label, single-arm studies, and case series. Several mAbs have shown potential antidepressant effects, but most studies in primary inflammatory disorders included patients with mild depression. Only infliximab and sirukumab were directly examined in individuals with primary depression. mAbs that do not require laboratory monitoring, such as ixekizumab and dupilumab, could hold potential promise if future studies establish their safety profile regarding suicide risk., Conclusions and Relevance: The use of several mAbs for the treatment of primary inflammatory disorders has been associated with improvement of comorbid depressive symptoms. Given their unique mechanisms of action, mAbs may offer a new hope for depressed patients who do not respond to currently available antidepressants. Further research addressing individuals with more severe depressive symptoms is essential. Direct examination of antidepressant effects of mAbs in people with primary depressive disorders is also crucial to refine their clinical use in the treatment of depression., (© Copyright 2024 Physicians Postgraduate Press, Inc.)

Objective: Suicidal ideation (SI) is a risk factor for completed suicide. Our previous resting state functional magnetic resonance imaging (fMRI) study found that higher amplitude of low frequency fluctuation (ALFF) in right hippocampus and thalamus was associated with SI in major depressive disorder (MDD). The present study aimed to evaluate that association in participants with bipolar disorder (BD)., Methods: Thirty depressed, adult participants with a DSM-IV diagnosis of BD had resting state fMRI scans. Region-of-interest (ROI) analyses used ALFF values within areas that were previously associated with SI in MDD. Spearman rank correlation and ordinal regression analyses were performed to assess associations between ALFF values and the SI item of the Montgomery-Asberg Depression Rating Scale. Exploratory whole-brain analyses identified regions where ALFF was associated with SI., Results: Within the right hippocampus region, SI was positively associated with ALFF (Spearman R  = 0.490, P  = .0060). Ordinal regression analysis indicated that for every 0.1-unit increase in ALFF in that region, the odds of having higher SI were increased by 35% (odds ratio = 1.35; 95% confidence interval, 1.08-1.73; P  = .012). Within the previously identified thalamus cluster, SI was associated with ALFF only at a trend level (Spearman R  = 0.310, P  = .069). Whole-brain analyses identified 3 clusters of positive association between SI and ALFF, 1 of which was located in the right hippocampus., Conclusions: This study found that our previous finding of positive association between SI and ALFF in the right hippocampus extended to bipolar depression. Future studies should examine the clinical utility of this association, and the role of the hippocampus in SI., Trial Registration: Data used for this secondary analysis came from studies with ClinicalTrials.gov identifiers NCT02239094 (January 2015 through September 2016) and NCT02473250 (January 2015 through December 2019)., (© Copyright 2022 Physicians Postgraduate Press, Inc.)

Objective: Subanesthetic ketamine rapidly reduces depressive symptoms and suicidal ideation in some depressed patients. Its effects on neurocognitive functioning in such individuals with significant suicidal ideation is not well understood, even though certain neurocognitive deficits are associated with suicide behavior beyond clinical symptoms., Methods: In this study, depressed patients with clinically significant suicidal ideation (n = 78) underwent neuropsychological testing before and 1 day after double-blind treatment with intravenous ketamine (n = 39) or midazolam (n = 39). A subgroup randomized to midazolam whose ideation did not remit after initial infusion received open ketamine and additional neurocognitive testing a day after this treatment. The primary outcome was change in performance on this neurocognitive battery. The study was conducted between November 2012 and January 2017., Results: Blinded ketamine produced rapid improvement in suicidal ideation and mood in comparison to midazolam, as we had reported previously. Ketamine, relative to midazolam, was also associated with specific improvement in reaction time (Choice RT) and interference processing/cognitive control (computerized Stroop task)-the latter a measure that has been associated with past suicide attempt in depression. In midazolam nonremitters later treated with open ketamine and retested, reaction time and interference processing/cognitive control also improved relative to both of their prior assessments. Neurocognitive improvement, however, was not correlated with changes in depression, suicidal thinking, or general mood., Conclusions: Overall, ketamine was found to have a positive therapeutic effect on neurocognition 1 day after treatment on at least 1 measure associated with suicidal behavior in the context of depression. Results suggest additional independent therapeutic effects for ketamine in the treatment of depressed patients at risk for suicidal behavior., Trial Registration: ClinicalTrials.gov identifier: NCT01700829., (© Copyright 2021 Physicians Postgraduate Press, Inc.)

Objective: About 45% of civilians who died by suicide had contact with a doctor within 1 month of death. Thus, educating primary care physicians (PCP) to detect and mitigate depression is an important suicide-prevention strategy. However, the PCP consulting rate before suicide has not been examined in a military population. We investigated the utilization of primary health care and mental health services by active-duty military personnel suicide cases prior to death in comparison to matched military controls., Method: All suicides (N = 170) were extracted from a cohort of all active-duty Israeli military male personnel between 2002 and 2012. Applying a retrospective, nested case-control design, we compared primary care services utilization by suicide cases with demographic and occupationally matched military controls (N = 500)., Results: Whereas 38.3% of suicide cases contacted a PCP within the last month before death, only 27.6% of suicide cases contacted a mental health specialist during their entire service time. The PCP contact rate within 1 month before death or index day did not differ between suicide cases and military controls (38.3% vs. 33.8%, χ²₁ = 1.05, P = .3). More suicide cases contacted a mental health specialist within service time than did military controls (27.6% vs. 13.6%, χ²₁ = 10.85, P = .001)., Conclusions: Even though PCP contact rate by military personnel who died by suicide is slightly lower than that reported for civilians who died by suicide prior to their death, it is higher than mental health specialist contact rate and higher than that by age-matched civilians who died by suicide. These results imply that PCPs education is a viable approach to suicide prevention in a military setting., (© Copyright 2014 Physicians Postgraduate Press, Inc.)

Objective: To investigate relationships of depressed parents' attachment style to offspring suicidal behavior., Method: 244 parents diagnosed with a DSM-IV depressive episode completed the Adult Attachment Questionnaire at study entry. Baseline and yearly follow-up interviews of their 488 offspring tracked suicidal behavior and psychopathology. Survival analysis and marginal regression models with correlated errors for siblings investigated the relationship between parent insecure attachment traits and offspring characteristics. Data analyzed were collected 1992-2008 during a longitudinal family study completed January 31, 2014., Results: Parental avoidant attachment predicted offspring suicide attempts at a trend level (P = .083). Parental anxious attachment did not predict offspring attempts (P = .961). In secondary analyses, anxious attachment in parents was associated with offspring impulsivity (P = .034) and, in offspring suicide attempters, was associated with greater intent (P = .045) and lethality of attempts (P = .003). Avoidant attachment in parents was associated with offspring impulsivity (P = .025) and major depressive disorder (P = .012). Parental avoidant attachment predicted a greater number of suicide attempts (P = .048) and greater intent in offspring attempters (P = .003). Results were comparable after adjusting for parent diagnosis of borderline personality disorder., Conclusions: Insecure avoidant, but not anxious, attachment in depressed parents may predict offspring suicide attempt. Insecure parental attachment traits were associated with impulsivity and major depressive disorder in all offspring and with more severe suicidal behavior in offspring attempters. Insecure parental attachment merits further study as a potential target to reduce risk of offspring psychopathology and more severe suicidal behavior., (© Copyright 2014 Physicians Postgraduate Press, Inc.)

Objective: Identifying the depression symptoms most closely associated with suicidal thoughts and which medications provide the fastest depression relief may help suicide prevention., Method: Post hoc analysis of data from a randomized, double-blind, 8-week clinical trial of the selective serotonin reuptake inhibitor paroxetine controlled release (n = 36) versus the norepinephrine-dopamine reuptake inhibitor bupropion extended release (n = 38) was conducted in patients with DSM-IV major depressive disorder and past suicide attempt or current suicidal thoughts. Treatment effects on Hamilton Depression Rating Scale (HDRS) and Beck Depression Inventory symptom clusters were compared. We hypothesized that paroxetine would demonstrate a superior effect on nonsuicidal, affective/cognitive depression symptom clusters that our prior work found to be associated with suicidal thoughts and attempts. Data were collected from February 2005 to January 2010., Results: There was a treatment main effect on HDRS psychic depression (depressed mood, guilt, retardation, helpless, hopeless, worthless) (estimate = -2.2; 95% CI, -3.2 to -1.1; t67.16 = -4.01; P < .001), one of the clusters most strongly correlated to suicidal ideation. The net drug effect demonstrated that mean psychic depression score was 2.2 points lower after 1 week of paroxetine compared to bupropion treatment. The significance level of this effect was P < .001 at weeks 1 and 2, P = .012 at week 3 and P = .051 at week 4. Results for other depression scale factors were nonsignificant (P > .05)., Conclusions: The results require replication but suggest a pathway by which selective serotonin reuptake inhibitor treatment may exert a stronger effect compared with norepinephrine-dopamine reuptake inhibitor treatment on reduction of suicidal thoughts during initial weeks of pharmacotherapy in these higher risk patients., Trial Registration: ClinicalTrials.gov identifier: NCT00429169., (© Copyright 2013 Physicians Postgraduate Press, Inc.)

Objective: To evaluate whether lifetime suicidal ideation with intention to act and/or suicidal behaviors reported at baseline predict risk of prospectively reporting suicidal behavior during subsequent study participation., Method: Data from studies using the electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) to prospectively monitor suicidal ideation and behaviors between September 2009 and May 2011 were analyzed. Studies included patients with major depressive disorder, insomnia, posttraumatic stress disorder, epilepsy, and fibromyalgia. Records for 35,224 eC-SSRS assessments were extracted. Incomplete assessments and eC-SSRS records from patients missing a baseline assessment or with no prospective follow-up assessments were excluded. Baseline lifetime eC-SSRS reports were categorized as negative (no lifetime ideation with intent to act or prior suicidal behavior) or positive (lifetime ideation with intent to act but no prior behavior, no ideation with intent to act but prior behavior, or both lifetime ideation with intent and prior behavior)., Results: 3,776 patients completed a baseline and 1 or more follow-up assessments. The mean follow-up period was 64 days. Of patients with negative lifetime reports, 2.4% subsequently reported suicidal behavior during study participation, compared to 12.0% of patients with lifetime ideation with intent only (OR = 5.55; 95% CI, 2.65-11.59), 9.6% of patients with lifetime behavior only (OR = 4.33; 95% CI, 2.94-6.39), and 18.3% of patients with both (OR = 9.13; 95% CI, 6.47-12.88). Sensitivity and specificity of positive reports for identifying suicidal behaviors were 0.67 and 0.76, respectively., Conclusions: Patients reporting lifetime suicidal ideation with intent to act and/or prior suicidal behavior at baseline are 4 to 9 times more likely to prospectively report suicidal behavior during study participation., (© Copyright 2013 Physicians Postgraduate Press, Inc.)

Background: Although lower levels of omega-3 polyunsaturated fatty acids (PUFAs) are found in major depressive disorder, less is known about PUFA status and anxiety disorders., Method: Medication-free participants with DSM-IV-defined major depressive disorder (MDD), with (n = 18) and without (n = 41) comorbid DSM-IV anxiety disorders, and healthy volunteers (n = 62) were recruited from October 2006 to May 2010 for mood disorder studies at the New York State Psychiatric Institute. Participants were 18-73 years of age (mean age, 35.8 ± 12.6 years). Depression and anxiety severity was assessed using depression and anxiety subscales from the 17-item Hamilton Depression Rating Scale. Plasma PUFAs eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid (DHA; 22:6n-3) and the ratio of arachidonic acid (AA; 22:4n-6) to EPA (AA:EPA) were quantified. This secondary analysis employed analysis of variance with a priori planned contrasts to test for diagnostic group differences in log-transformed PUFA levels (logDHA, logEPA, and logAA:EPA)., Results: Plasma levels of logDHA (F(2,118) = 4.923, P = .009), logEPA (F(2,118) = 6.442, P = .002), and logAA:EPA (F(2,118) = 3.806, P = .025) differed across groups. Participants with MDD had lower logDHA (t(118) = 2.324, P = .022) and logEPA (t(118) = 3.175, P = .002) levels and higher logAA:EPA levels (t(118) = -2.099, P = .038) compared with healthy volunteers. Lower logDHA (t(118) = 2.692, P = .008) and logEPA (t(118) = 2.524, P = .013) levels and higher logAA:EPA levels (t(118) = -2.322, P = .022) distinguished anxious from nonanxious MDD. Depression severity was not associated with PUFA plasma levels; however, anxiety severity across the entire sample correlated negatively with logDHA (r(p) = -0.22, P = .015) and logEPA (r(p) = -0.25, P = .005) levels and positively with logAA:EPA levels (r(p) = 0.18, P = .043)., Conclusions: The presence and severity of comorbid anxiety were associated with the lowest EPA and DHA levels. Further studies are needed to elucidate whether omega-3 PUFA supplementation may preferentially alleviate MDD with more severe anxiety., (© Copyright 2013 Physicians Postgraduate Press, Inc.)

Objective: To examine the demographic and clinical correlates of nonsuicidal self-injury., Method: This is a cross-sectional analysis of a longitudinal cohort study of the familial transmission of suicidal behavior, conducted at referral centers in Pittsburgh, Pennsylvania, and New York, New York. Participants included 291 probands with DSM-IV mood disorder, one-half of whom had attempted suicide, and 507 of their offspring. The primary outcome assessed was nonsuicidal self-injury in offspring. Psychosocial correlates of nonsuicidal self-injury were determined by comparing personal, parental, and familial characteristics of offspring with and without nonsuicidal self-injury, assessed using a variety of interview and self-report measures at study entry. Data were collected between August 1998 and August 2007., Results: Of 507 offspring, 7.7% (n=39) had engaged in nonsuicidal self-injury. The most salient correlates of nonsuicidal self-injury on multivariate logistic regression were diagnosis of depression (OR=3.78, P<.001) and greater aggression (OR=1.07, P=.01), depressive symptoms (OR=1.59, P=.009), and suicidal ideation (OR=1.24, P=.004). Parental history of abuse, as well as family histories of suicide attempt and nonsuicidal self-injury, was noncontributory., Conclusions: Nonsuicidal self-injury is associated with the presence and severity of depression, suicidal ideation, and behavioral dysregulation. On multivariate analysis, only individual predictors remained significant; this result is distinct from that for correlates of suicide attempt reported in this sample, for which familial variables played a significant role., (© Copyright 2012 Physicians Postgraduate Press, Inc.)

Objective: To determine the demographic and clinical predictors of nonsuicidal self-injury and to examine the longitudinal relationship between nonsuicidal self-injury and suicide attempt., Method: This was a longitudinal cohort study of the familial transmission of suicidal behavior. The sample consisted of probands with DSM-IV mood disorder (n = 212), 54.2% of whom were suicide attempters, and their offspring aged at least 10 years (n = 352), followed for a mean of 3.8 years. Personal, parental, and familial characteristics were assessed annually to identify the most parsimonious subset of these variables associated with nonsuicidal self-injury, the primary outcome. Data were collected between August 1998 and August 2007., Results: Of 352 offspring, 7.4% (n = 26) engaged in nonsuicidal self-injury during follow-up. In the final model examining predictors at baseline, the most severe time point, and the time point prior to nonsuicidal self-injury, only predictors from the most proximal time point were significant, namely younger age (odds ratio [OR] = 0.75, P = .002), diagnosis of current major depression (OR = 5.09, P < .001), and suicidal ideation (OR = 1.46, P = .02). In 2 of the 3 single time point models, baseline nonsuicidal self-injury was the most significant predictor of nonsuicidal self-injury during follow-up. Suicide attempt was predicted by both baseline nonsuicidal self-injury and suicide attempt, but when both were included in the model, nonsuicidal self-injury was a significant predictor (OR = 7.50, P = .009), but suicide attempter was not (OR = 3.78, P = .08); offspring aggression (OR = 1.11, P = .01) predicted suicide attempt but not nonsuicidal self-injury. Parental histories of nonsuicidal self-injury, suicide attempt, and abuse were not predictive of nonsuicidal self-injury., Conclusions: Nonsuicidal self-injury may be an earlier manifestation of a shared diathesis with suicide attempt, consisting of depression and suicidal ideation, and that diathesis may lead to suicidal behavior in the face of greater offspring aggression and family pathology. The apparent bidirectional temporal relationship between nonsuicidal self-injury and suicide attempt may be explained by this shared diathesis., (© Copyright 2012 Physicians Postgraduate Press, Inc.)

Objective: Randomized trials of omega-3 polyunsaturated fatty acid (PUFA) treatment for depression have differed in outcome. Recent meta-analyses ascribe discrepancies to differential effects of eicosapentaenoic acid (EPA) versus docosahexaenoic acid (DHA) and to diagnostic heterogeneity. This meta-analysis tests the hypothesis that EPA is the effective component in PUFA treatment of major depressive episodes., Data Sources: PubMed/MeSH was searched for studies published in English from 1960 through June 2010 using the terms fish oils (MeSH) AND (depressive disorder [MeSH] OR bipolar depression) AND randomized controlled trial (publication type). The search was supplemented by manual bibliography review and examination of relevant review articles., Study Selection: The search yielded 15 trials involving 916 participants. Studies were included if they had a prospective, randomized, double-blinded, placebo-controlled study design; if depressive episode was the primary complaint (with or without comorbid medical conditions); if omega-3 PUFA supplements were administered; and if appropriate outcome measures were used to assess depressed mood., Data Extraction: Extracted data included study design, sample sizes, doses and percentages of EPA and DHA, mean ages, baseline and endpoint depression ratings and standard deviations for PUFA and placebo groups, and P values. The clinical outcome of interest was the standardized mean difference in the change from baseline to endpoint scores on a depression rating scale in subjects taking PUFA supplements versus subjects taking placebo., Data Synthesis: In a mixed-effect model, percentage of EPA in the supplements was the fixed-effect predictor, dichotomized into 2 groups: EPA < 60% or EPA ≥ 60% of the total EPA + DHA. Secondary analyses explored the relevance of treatment duration, age, and EPA dose., Results: Supplements with EPA ≥ 60% showed benefit on standardized mean depression scores (effect size = 0.532; 95% CI, 0.277-0.733; t = 4.195; P < .001) versus supplements with EPA < 60% (effect size = -0.026; 95% CI, -0.200 to 0.148; t = -0.316; P = .756), with negligible contribution of random effects or heteroscedasticity and with no effects of treatment duration or age. Supplements with EPA < 60% were ineffective. Exploratory analyses supported a nonlinear model, with improvement determined by the dose of EPA in excess of DHA, within the range of 200 to 2,200 mg/d of EPA., Conclusions: Supplements containing EPA ≥ 60% of total EPA + DHA, in a dose range of 200 to 2,200 mg/d of EPA in excess of DHA, were effective against primary depression. Translational studies are needed to determine the mechanisms of EPA's therapeutic benefit., (© Copyright 2011 Physicians Postgraduate Press, Inc.)

Objective: Patients with bipolar disorder are prone to suicidal behavior, yet possible protective mechanisms are rarely studied. We investigated a possible protective role for moral or religious objections to suicide against suicidal ideation and attempts in depressed bipolar patients., Method: A retrospective case control study of 149 depressed bipolar patients (DSM-III-R criteria) in a tertiary care university research clinic was conducted. Patients who reported religious affiliation were compared with 51 patients without religious affiliation in terms of sociodemographic and clinical characteristics and history of suicidal behavior. The primary outcome measure was the moral or religious objections to suicide subscale of the Reasons for Living Inventory (RFLI)., Results: Religiously affiliated patients had more children and more family-oriented social networks than nonaffiliated patients. As for clinical variables, religiously affiliated patients had fewer past suicide attempts, had fewer suicides in first-degree relatives, and were older at the time of first suicide attempt than unaffiliated patients. Furthermore, patients with religious affiliation had comparatively higher scores on the moral or religious objections to suicide subscale of the RFLI, lower lifetime aggression, and less comorbid alcohol and substance abuse and childhood abuse experience. After controlling for confounders, higher aggression scores (P = .001) and lower score on the moral or religious objections to suicide subscale of the RFLI (P < .001) were significantly associated with suicidal behavior in depressed bipolar patients. Moral or religious objections to suicide mediated the effects of religious affiliation on suicidal behavior in this sample., Conclusions: Higher score on the moral or religious objections to suicide subscale of the RFLI is associated with fewer suicidal acts in depressed bipolar patients. The strength of this association was comparable to that of aggression scores and suicidal behavior, and had an independent effect. A possible protective role of moral or religious objections to suicide deserves consideration in the assessment and treatment of suicidality in bipolar disorder., (© Copyright 2011 Physicians Postgraduate Press, Inc.)

Objective: To estimate the relationship between antiallergy drug prescription rates and suicide across the United States and over time. The relationship between allergy, allergens, and suicidal behavior and suggestions of a possible immune mediation led us to hypothesize that intranasal corticosteroids, known to reduce local airway production of T-helper cell type 2 cytokines, may be associated with reduced risk of suicide relative to antihistamines, which only secondarily affect cytokine production., Method: The authors evaluated the relationship of suicide rates at the county level in the United States (N = 120,076 suicides) with prescriptions for intranasal corticosteroids and nonsedating antihistamines, in interaction with antidepressant prescriptions and other socioeconomic variables, for the period from 1999 to 2002. Suicide rate data were derived from state vital record systems based on local death certificate registries, and county-level allergy and antidepressant prescription data were obtained from IMS Health Incorporated (Plymouth Meeting, Pennsylvania)., Results: The prescription volume of intranasal corticosteroids was associated with a lower suicide risk (P = .0004), while that of antihistamines was associated with a modestly greater suicide risk (P = .0001). Adjustment for antidepressant prescriptions did not affect these relationships., Conclusions: This is the first study, to our knowledge, to find a possible association between completed suicide and medications for allergic rhinitis and also the first report of an association of intranasal corticosteroid use with a lower suicide rate. This association should be considered preliminary and deserving of further investigation., (© Copyright 2011 Physicians Postgraduate Press, Inc.)

Objective: To address issues concerning potential treatment-emergent "suicidality," a consensus conference was convened March 23-24, 2009., Participants: This gathering of participants from academia, government, and industry brought together experts in suicide prevention, clinical trial design, psychometrics, pharmacoepidemiology, and genetics, as well as research psychiatrists involved in studies in studies of psychiatric disorders associated with elevated suicide risk across the life cycle. The process involved reviews of the relevant literature, and a series of 6 breakout sessions focused on specific questions of interest., Evidence: Each of the participants at the meeting received references relevant to the formal presentations (as well as the slides for the presentations) for their review prior to the meeting. In addition, the assessment instruments of suicidal ideation/behavior were reviewed in relationship to standard measures of validity, reliability, and clinical utility, and these findings were discussed at length in relevant breakout groups, in the final plenary session, and in the preparation of the article. Consensus and dissenting views were noted., Consensus Process: Discussion and questions followed each formal presentation during the plenary sessions. Approximately 6 questions per breakout group were prepared in advance by members of the Steering Committee and each breakout group chair. Consensus in the breakout groups was achieved by nominal group process. Consensus recommendations and any dissent were reviewed for each breakout group at the final plenary session. All plenary sessions were recorded and transcribed by a court stenographer. Following the transcript, with input by each of the authors, the final paper went through 14 drafts. The output of the meeting was organized into this brief report and the accompanying full article from which it is distilled. The full article was developed by the authors with feedback from all participants at the meeting and represents a consensus view. Any areas of disagreement at the conference have been noted in the text., Conclusions: The term suicidality is not as clinically useful as more specific terminology (ideation, behavior, attempts, and suicide). Most participants applauded the FDA's encouragement of standard definitions and definable expectations for investigators and industry sponsors. Further research of available assessment instruments is needed to verify their utility, reliability, and validity in identifying suicide-associated treatment-emergent adverse effects and/or a signal of efficacy in suicide prevention trials. The FDA needs to systematically monitor postmarketing events by encouraging the development of a validated instrument for postmarketing surveillance of suicidal ideation, behavior, and risk. Over time, the FDA, industry, and clinical researchers should evaluate the impact of the requirement that all central nervous system clinical drug trials must include a Columbia Classification Algorithm of Suicide Assessment (C-CASA)-compatible screening instrument for assessing and documenting the occurrence of treatment-emergent suicidal ideation and behavior. Finally, patients at high risk for suicide can safely be included in clinical trials, if proper precautions are followed., (Copyright 2010 Physicians Postgraduate Press, Inc.)

Objective: To address issues concerning potential treatment-emergent "suicidality," a consensus conference was convened March 23-24, 2009., Participants: This gathering of participants from academia, government, and industry brought together experts in suicide prevention, clinical trial design, psychometrics, pharmacoepidemiology, and genetics, as well as research psychiatrists involved in studies of major depression, bipolar disorder, schizophrenia, substance abuse/dependence, and other psychiatric disorders associated with elevated suicide risk across the life cycle. The process involved reviews of the relevant literature, and a series of 6 breakout sessions focused on specific questions of interest., Evidence: Each of the participants at the meeting received references relevant to the formal presentations (as well as the slides for the presentations) for their review prior to the meeting. In addition, the assessment instruments of suicidal ideation/behavior were reviewed in relationship to standard measures of validity, reliability, and clinical utility, and these findings were discussed at length in relevant breakout groups, in the final plenary session, and in the preparation of the article. Consensus and dissenting views were noted., Consensus Process: Discussion and questions followed each formal presentation during the plenary sessions. Approximately 6 questions per breakout group were prepared in advance by members of the Steering Committee and each breakout group chair. Consensus in the breakout groups was achieved by nominal group process. Consensus recommendations and any dissent were reviewed for each breakout group at the final plenary session. All plenary sessions were recorded and transcribed by a court stenographer. Following the transcript, with input by each of the authors, the final paper went through 14 drafts. The output of the meeting was organized into this scholarly article, which has been developed by the authors with feedback from all participants at the meeting and represents a consensus view. Any areas of disagreement have been noted., Conclusions: The term suicidality is not as clinically useful as more specific terminology (ideation, behavior, attempts, and suicide). Most participants applauded the FDA's effort to promote standard definitions and definable expectations for investigators and industry sponsors by endorsing the terminology in the Columbia Classification Algorithm of Suicide Assessment (C-CASA). Further research of available assessment instruments is needed to verify their utility, reliability, and validity in identifying suicide-associated treatment-emergent adverse effects and/or a signal of efficacy in suicide prevention trials. The FDA needs to build upon its new authority to systematically monitor postmarketing events by encouraging the development of a validated instrument for postmarketing surveillance of suicidal ideation, behavior, and risk within informative large health care-related databases in the United States and abroad. Over time, the FDA, industry, and clinical researchers should evaluate the impact of the current Agency requirement that all CNS clinical drug trials must include a C-CASA-compatible screening instrument for assessing and documenting the occurrence of treatment-emergent suicidal ideation and behavior. Finally, patients at high risk for suicide can safely be included in clinical trials, if proper precautions are followed, and they need to be included to enable premarket assessments of the risks and benefits of medications related to suicidal ideation, suicidal behavior, and suicide in such patients., (Copyright 2010 Physicians Postgraduate Press, Inc.)

Background: The development of new antidepressant drugs has reached a plateau. There is an unmet need for faster, better, and safer medications, but as placebo-response rates rise, effect sizes shrink, and more studies fail or are negative, pharmaceutical companies are increasingly reluctant to invest in new drug development because of the risk of failure. In the absence of an identifiable human pathophysiology that can be modeled in preclinical studies, the principal point of leverage to move beyond the present dilemma may be improving the information gleaned from well-designed proof-of-concept (POC) studies of new antidepressant drugs with novel central nervous system effects. With this in mind, a group of experts was convened under the auspices of the University of Arizona Department of Psychiatry and Best Practice Project Management, Inc., Participants: Forty-five experts in the study of antidepressant drugs from academia, government (U.S. Food and Drug Administration and National Institute of Mental Health), and industry participated. EVIDENCE/CONSENSUS PROCESS: In order to define the state of clinical trials methodology in the antidepressant area, and to chart a way forward, a 2-day consensus conference was held June 21-22, 2007, in Bethesda, Md., at which careful reviews of the literature were presented for discussion. Following the presentations, participants were divided into 3 workgroups and asked to address a series of separate questions related to methodology in POC studies. The goals were to review the history of antidepressant drug trials, discuss ways to improve study design and data analysis, and plan more informative POC studies., Conclusions: The participants concluded that the federal government, academic centers, and the pharmaceutical industry need to collaborate on establishing a network of sites at which small, POC studies can be conducted and resulting data can be shared. New technologies to analyze and measure the major affective, cognitive, and behavioral components of depression in relationship to potential biomarkers of response should be incorporated. Standard assessment instruments should be employed across studies to allow for future meta-analyses, but new instruments should be developed to differentiate subtypes and symptom clusters within the disorder that might respond differently to treatment. Better early-stage POC studies are needed and should be able to amplify the signal strength of drug efficacy and enhance the quality of information in clinical trials of new medications with novel pharmacologic profiles., (Copyright 2008 Physicians Postgraduate Press, Inc.)

Objective: Alcohol use and depressive disorders are frequently comorbid. Few studies have assessed the impact of comorbid alcohol use disorders (AUDs) on clinical aspects of major depression. We compared depressed subjects with and without co-occurring AUDs with respect to demographic and clinical parameters., Method: 505 individuals participated. 318 subjects had DSM-IV major depressive disorder (MDD) without a history of any alcohol or substance abuse/dependence (MDD only), and 187 individuals had MDD and a history of alcohol abuse/dependence (MDD/AUD). Demographic, clinical, and psychiatric history measures of patients in the 2 groups were examined and compared. The study was conducted from January 1990 to June 2005., Results: MDD/AUD patients were younger at their first psychiatric hospitalization (p = .014), their first major depressive episode (p = .041), and their first suicide attempt (p = .001). They reported more previous major depressive episodes (p = .001), suicide attempts (p = .001), and recent life events (p = .001); and had higher lifetime aggression (p < .001), impulsivity (p < .001), and hostility (p < .001) scores. MDD/AUD patients were also more likely to report tobacco smoking (p < .001), a lifetime history of abuse (p = .004), and a history of AUD among first-degree relatives (p < .001) compared to MDD only patients. MDD/AUD individuals also had higher childhood (p < .001), adolescent (p < .001), and adult (p < .001) aggression scores and reported more behavioral problems during their childhood compared to their counterparts. Logistic regression analysis demonstrates that the number of previous depressive episodes, lifetime aggression, and smoking drive the difference between the groups., Conclusions: Our findings suggest that comorbid MDD/AUD may result from worse antecedents and lead to early onset, more comorbidity, and a more severe course of illness.

Background: Self-reported childhood sexual abuse is associated with major depression and with suicidal behavior. The current study investigates the relationship between reported childhood abuse and the familial transmission of suicidal behavior and other related risk factors., Method: 507 offspring of 271 parent probands with DSM-IV major depressive disorder were compared according to the reported childhood abuse history on demographic, diagnostic, and clinical variables related to risk for suicidal behavior. Both self-report and clinical interview measures assessed history of childhood physical and sexual abuse. The study was conducted from May 1997 to February 2004., Results: Reported childhood sexual abuse, but not physical abuse, in the proband correlated with suicide attempts, posttraumatic stress disorder, earlier onset of major depressive disorder, higher levels of impulsivity, and greater likelihood of childhood sexual abuse in the offspring and was rarely perpetrated by the affected parent. A reported history of childhood physical abuse was related to more lifetime aggression in the offspring., Conclusions: Reported childhood sexual abuse is a risk factor for suicidal behavior in parent and offspring. Transmission of suicide risk across generations is related to the familial transmission of sexual abuse and impulsivity. Sexual abuse is not directly transmitted by the victim to the next generation and may be related to family dynamics related to sexual abuse.

Objective: Determining risk for a suicide attempt in psychiatric patients requires assessment of multiple risk factors and knowledge of their relative importance. Classification and regression tree (CART) analysis generates decision trees that select the variables that perform best in identifying the group of interest and model clinical decision making. Hypothetical decision trees to identify recent and remote suicide attempters, weighted to increase sensitivity, were generated for psychiatric patients using correlates of past suicidal behavior., Method: Correlates of past suicide attempts were identified in 408 patients with mood, schizophrenia spectrum, or personality disorders (DSM-IV). Correlated variables were entered into recursive partitioning statistical models to generate equally weighted and unequally weighted hypothetical decision trees for distinguishing recent ( 250 days prior to study) suicide attempters from nonattempters. The study was conducted from December 1989 to November 1998., Results: In equally weighted trees, a recent past suicide attempt was best predicted by current suicidal ideation (sensitivity = 56%, specificity = 91%, positive predictive value = 69%), and no adequate model was found for remote attempts. In unequally weighted models, recent attempters were identified by suicidal ideation and comorbid borderline personality disorder (sensitivity = 73%, specificity = 80%, positive predictive value = 58%). Remote attempters were identified by lifetime aggression and current subjective depression (sensitivity = 89%, specificity = 36%, positive predictive value = 44%)., Conclusion: Current suicidal ideation is the best indicator of a recent suicide attempt in psychiatric patients. Indicators of a remote attempt are aggressive traits and current depression. Weighted decision trees can improve sensitivity and miss fewer attempters but with a cost in specificity.

Objective: To determine whether borderline personality disorder (BPD) and bipolar II disorder can be differentiated from each other and from major depressive disorder (MDD) by comparing depression severity, impulsiveness, and hostility in mood disorder patients with and without BPD., Method: One hundred seventy-three patients with either MDD or bipolar II disorder were enrolled from a larger sample admitted to a multisite project on mood disorders and suicidal behavior conducted from June 1996 through June 2006. Patients were divided into 4 groups: MDD with BPD, MDD without an Axis II diagnosis, bipolar II disorder with BPD, and bipolar II disorder without an Axis II diagnosis. All diagnoses were based on DSM-IV criteria. Depression was assessed using the 17-item Hamilton Rating Scale for Depression (HAM-D) and the self-rated Beck Depression Inventory (BDI). Impulsiveness was assessed using the Barratt Impulsiveness Scale, and hostility was assessed using the Buss-Durkee Hostility Inventory., Results: Patients with BPD reported higher levels of impulsiveness (p = .004) and hostility (p = .001), independent of Axis I diagnosis. Bipolar II patients reported greater attentional impulsiveness (p = .008) than MDD patients, independent of BPD status, while BPD patients reported greater nonplanning impulsiveness than patients without BPD, independent of Axis I diagnosis (p = .02). For motor impulsiveness, there was a main effect for Axis I diagnosis (p = .05) and Axis II diagnosis (p = .002). The bipolar II + BPD group scored the highest, suggesting a compound effect of comorbidity. There were no differences in depression severity when measured with the HAM-D, although the BPD groups reported more severe depression on the BDI, independent of their Axis I diagnosis (p = .05). The BPD groups scored higher on the cognitive factor (p = .01) and anxiety factor (p = .03) of the HAM-D., Conclusion: Results suggest that there is a unique symptom and trait profile associated with BPD that distinguishes the diagnosis from bipolar II disorder. Results also suggest that impulsiveness is an important aspect of both disorders and that there is a compounding effect associated with a diagnosis of bipolar II disorder with comorbid BPD.

Objective: We examined the relationship of increasing prescription volume of newer antidepressants, introduced in Japan in 1999, to national rates of suicide., Method: The relationship between annual changes in rates of suicide (obtained from the Japanese Ministry of Health, Labor, and Welfare Vital Statistics Database) and prescription volume of the newer antidepressants paroxetine, fluvoxamine, and milnacipran (obtained from the database of IMS Japan K.K.), stratified by gender and age groups, was modeled statistically for the years 1999 through 2003. Effects of unemployment and alcohol consumption and the interaction of gender and age with antidepressant prescribing were assessed., Results: From 1999 through 2003 in Japan, total antidepressant prescriptions increased 57% among males and 50% among females. Approximately 80% of this increase involved the selective serotonin reuptake inhibitors (SSRIs). To reduce a limitation of ecological analysis, we compared annual change in prescription and suicide rates, which eliminates the effect of long-term (secular) linear trends. We found an inverse association between year-to-year changes in the suicide rate and prescription volume of newer antidepressants (fluvoxamine, paroxetine, and milnacipran) (beta = -1.34, p = .008) and SSRIs specifically (fluvoxamine, paroxetine) (beta = -1.41, p = .019). An increase of 1 defined daily dose of SSRI use/1000 population/day was associated with a 6% decrease in suicide rate. Exploratory analysis suggested a stronger association in males, who experienced a greater increase in antidepressant use. Changes in unemployment and alcohol consumption rates did not explain the association., Conclusion: In Japan during 1999 through 2003, absent long-term linear trend effects, annual increases in prescribing of newer antidepressant medications, mainly SSRIs, were associated with annual decreases in suicide rates, particularly among males.

Objective: Patients with cluster B personality disorder (CBPD) are particularly prone to suicidal behavior, yet possible protective mechanisms are not often studied. The present study investigated a possible protective role of moral objections to suicide (MOS) against suicidal behavior in patients with CBPD and current depression. The effect of MOS was then examined in relation to other mechanisms affecting suicide risk including trait aggressivity and the presence of effective coping strategies., Method: 147 depressed patients with comorbid CBPD (DSM-III-R) were compared with 210 depressed patients without CBPD in terms of their history of suicide attempts and clinical and demographic characteristics. The relationship of MOS to suicide attempt was examined by logistic regression controlling for demographic and clinical differences between the groups as well as presence of comorbid CBPD. Data were collected from 1990 to 2003., Results: Subjects with comorbid CBPD had fewer MOS and reported more previous suicide attempts. In logistic regression, fewer MOS/religious beliefs, lower coping potential, and higher aggression level were associated with suicide attempt. A CBPD diagnosis did not affect the relationship between MOS and suicide attempts., Conclusions: The results of this study suggest that the presence of MOS/religious beliefs may have a protective effect against suicidal behavior in depressed patients with comorbid CBPD and may be a target for therapeutic intervention.

Objective: Published results from a U.S. study of depressed suicide attempters and a Madrid, Spain, study including all consecutively admitted suicide attempters suggested that aggression scores were higher in U.S. attempters. This observation led us to compare depressed attempters and controls from both suicide research centers and explore whether New York City (NYC) patients carry out suicidal acts of greater lethality than patients in Madrid. The study goals were (1) to compare aggression scores in attempters and healthy volunteers between the 2 cities and (2) to determine whether higher aggression scores are associated with greater medical lethality of suicide attempts., Method: The respective samples from NYC and Madrid included attempters with a DSM-IV diagnosis of major depressive disorder (N = 117 and N = 133) and healthy controls (N = 90 and N = 317). Aggression scores, measured by the Brown-Goodwin Scale, in attempters and healthy volunteers from both sites were compared using an analysis of variance model. The relationship between lethality of suicidal acts and aggression scores in attempters was assessed using logistic regression analyses. NYC subjects were recruited from 1998 to 2001, and Madrid subjects were selected from consecutive admissions in 1999., Results: Depressed suicide attempters from NYC made attempts of greater lethality and reported more lifetime aggressive behavior than depressed attempters in Madrid. NYC healthy volunteers also reported more aggression than their Madrid counterparts., Conclusions: This pilot study suggests that the greater lethality of suicidal behavior in NYC compared to Madrid is related to higher aggression levels, although the data have limitations. Cross-cultural studies are needed to verify whether aggression and higher lethality suicide attempts share a common diathesis explaining the higher suicide rates in NYC.

Background: The role of antidepressants in suicide prevention is a major public health question. An association was hypothesized between the increase in the use of non-tricyclic antidepressant medications in the United States and the decline in the suicide rate during the years 1985-1999., Method: The relationships between the suicide, antidepressant prescription, unemployment, and alcoholic beverage consumption rates were studied using generalized linear models. Suicide rates by antidepressant overdose were compared in selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs)., Results: From 1985 to 1999, the suicide rate fell 13.5%, with a greater decline among women, and antidepressant prescription rates increased over 4-fold, with the increase mostly due to SSRIs. Prescription rates for SSRIs and other second-generation antidepressants were both inversely associated with suicide rates (p = .03 and p = .02, respectively). In a multivariable analysis adjusting for unemployment and alcoholic beverage consumption rates, SSRI antidepressant prescription rates remained inversely associated with the national suicide rate (p = .03). Females received twice as many antidepressant prescriptions compared with males. The commonest prescription indication was mood disorders, the condition most often associated with suicide. SSRIs were associated with a lower risk of suicide by antidepressant overdose compared with TCAs., Conclusion: The decline in the national suicide rate (1985-1999) appears to be associated with greater use of non-tricyclic antidepressants. Treatment of a greater proportion of mood disorders with SSRIs and other second-generation non-tricyclic antidepressants may further reduce the suicide rate. Controlled studies of the antisuicidal properties of antidepressants are needed in high-risk depressed patient populations.

Background: We examined the presence of command auditory hallucinations for suicide (CAHS) in a sample of individuals with schizophrenia or schizoaffective disorder. We examined the relationship between CAHS and demographic and clinical variables. We also investigated the relationship between CAHS and suicide attempts., Method: 100 individuals with DSM-IV schizophrenia or schizoaffective disorder hospitalized on an inpatient research unit participated. Information was gathered using the Diagnostic Interview for Genetic Studies and the Harkavy Asnis Suicide Scale. Data were gathered from 1995 to 2001., Results: CAHS were frequent in this sample (22%), as were suicide attempts (33%). Eight percent of the entire sample (36% of those who experienced CAHS) made at least 1 suicide attempt in response to the hallucinations. The presence of CAHS was not related to demographic or clinical measures assessed. The frequency of CAHS was not statistically different for suicide attempters (30%) and nonattempters (18%). However, 80% (8/10) of attempters with CAHS reported at least 1 attempt in response to CAHS. Three of 6 repeat attempters who made at least 1 suicide attempt in response to CAHS also made other attempts that were not in response to CAHS. The presence of CAHS was not associated with a history of depression or substance abuse/dependence., Conclusion: The presence of CAHS does not directly predict suicide attempts. However, individuals who are already at risk for suicidal behavior (e.g., past attempters) may be at increased risk for a suicide attempt when experiencing CAHS.

Background: Major depression is often treated with medications in doses that are too low or too short in duration. We published an early version of the Antidepressant Treatment History Form (ATHF) that rates the adequacy of antidepressant treatment. The updated ATHF presented here includes newer medications and a computer algorithm to automate the evaluation of the adequacy of pharmacotherapy or electroconvulsive therapy for depression., Method: The computer algorithm was written in MS-DOS Q-BASIC and in Visual Basic 5.0. Treatment data from 47 depressed (Structured Clinical Interview for DSM-III-R) patients were scored by the computer algorithm and assigned a number from 0 to 5 for the adequacy of antidepressant treatment. A psychiatrist blinded to the computer ratings manually rated the treatment using the ATHF., Results: The computer algorithm, based on an updated version of the ATHF, estimates the adequacy of treatment of unipolar and bipolar depression. Computer algorithm results agreed with those generated by a clinician completing the form manually (kappa = 0.88 to 1.00)., Conclusion: The computer algorithm can be used to analyze large databases and may help reduce the morbidity and mortality associated with major depression by improving the assessment of adequacy of pharmacologic treatments for research and quality assurance purposes. The availability of the updated ATHF on the Internet for downloading allows for modifications according to the user's purposes.

Background: Electroconvulsive therapy (ECT) is the treatment of choice in some older patients with severe depression. When compared with younger depressed patients, older patients have been shown to be as likely to respond to ECT but more likely to develop cognitive impairment. This study addresses whether adults aged 50 years and over who have already failed to respond to at least 5 moderate-charge right unilateral (RUL) ECT treatments (150% above seizure threshold) are more likely to benefit from a switch to high-charge RUL ECT (450% above threshold) or to bilateral (BL) ECT., Method: Twenty-four patients who were treated with 5 to 8 moderate-charge RUL ECT treatments and who failed to improve sufficiently were randomly assigned to receive either BL ECT (N = 11) or high-charge RUL ECT (N = 13). Depressive (24-item Hamilton Rating Scale for Depression) and cognitive scores (Mini-Mental State Examination [MMSE]) were compared under double-blind conditions at 3 phases of treatment., Results: Patients in the BL ECT group exhibited significantly greater cognitive impairment (mean MMSE score decrease of 1.13) than those receiving high-charge RUL ECT (mean MMSE increase of 1.71). There were no statistically significant differences in clinical response to BL or high-charge RUL ECT (63.6% and 61.5%, respectively) or in depressive symptom remission (18.1% and 46.2%)., Conclusion: These results suggest that older patients who fail to respond to moderate-charge RUL ECT may benefit from a switch to high-charge RUL ECT rather than BL ECT. Larger future studies will be needed to compare clinical response in patients switched from moderate-dose RUL ECT to higher-dose RUL or to BL ECT.

Bipolar patients have been shown to be at high risk for suicidal behavior. Therefore, identifying potentially suicidal patients is necessary in the treatment of bipolar patients. A stress-diathesis model for suicidal behavior has been proposed to assist clinicians in determining which patients are at risk. In the model, suicidal behavior is the result of the interaction between an individual's threshold for suicidal acts and the stressors that can lead to suicidal behavior. Suicide risk factors can then be categorized as either diathesis-related or stress-related. In a study applying the model of suicidal behavior to bipolar disorder, bipolar patients who attempted suicide had higher levels of suicidal ideation, lifetime aggression, and substance abuse than the comparison group of nonattempters. Attempters had twice the number of major depressive episodes. Once high-risk patients are identified, their suicide risk can be managed through treatments such as prophylactic lithium treatment and other pharmacologic approaches.

Suicidal behavior has neurobiological determinants independent of the psychiatric illnesses with which it is associated. We have found that some patients with major depression are vulnerable to acting on suicidal impulses. This vulnerability results from the interaction between triggers or precipitants and the threshold for suicidal behavior. An important factor in setting an individual's threshold for acting on suicidal impulses is brain serotonergic function. Serotonin function has been shown to be lower in suicide attempters by studies measuring serotonin metabolites in cerebrospinal fluid and studies of prolactin response to fenfluramine. Postmortem studies of suicide victims also reveal decreased serotonin activity in the ventrolateral prefrontal cortex. New neuroimaging paradigms, such as positron emission tomography (PET), offer an opportunity to visualize serotonin function in vivo in a more direct way than has previously been available. This technology may provide the possibility of timely therapeutic intervention in patients at high risk for suicide.

The comparative efficacy of molindone and haloperidol, given by injection for the first 2-3 days of hospitalization and then continued orally for up to 4 weeks, is reported from an ongoing double-blind study. Efficacy and side effects were assessed by the Brief Psychiatric Rating Scale, Clinical Global Impressions, Treatment Emergent Symptom Scale, and Target Symptom Ratings. Analyses based on the first 35 patients who entered the study indicate that both drugs were effective and well tolerated. There were slight advantages for molindone early during the injectable phase of treatment and for haloperidol late during the oral portion of the study, but these differences were not clinically significant. No significant differences in side effects were found between the two drugs.

Suicide is a significant cause of mortality in patients suffering from major affective disorders, schizophrenia, and alcoholism. Generally, several clinical and psychosocial factors combine to result in suicide. These risk factors have high sensitivity but low specificity; only a small minority of patients who meet risk criteria actually complete suicide. Therefore, clinicians have had great difficulty in assessing suicide risk; more clinically useful risk indicators are crucially needed. Biologic markers such as low cerebrospinal fluid levels of the serotonin metabolite 5-hydroxyindoleacetic acid and related indices of serotonergic function appear to correlate with violent and impulsive suicidal behavior. These and other biologic changes may have predictive value in determining suicide risk, as well as contributing to the formulation of a more complete model to explain suicidal behavior that combines genetic, biologic, psychologic, and social factors.

Several selective and reversible monoamine oxidase inhibitors (MAOIs) have recently become available. Preliminary studies suggest that these compounds have antidepressant effects and may offer significant safety and side effect advantages over classical MAOIs. Pilot studies with 1-deprenyl, a selective MAO-B inhibitor, indicate that it may be most effective for patients with nonendogenous depression and for those (endogenous or nonendogenous) who present with certain reverse vegetative signs. The drug appears ineffective in depressed patients with associated panic attacks and phobic symptoms. An alternative approach in the development of safer, effective MAOIs is the use of rapidly reversible MAO-A inhibitors, such as moclobemide, that carry less risk of a hypertensive reaction and yet appear to be effective antidepressants. As selective MAO-A and MAO-B inhibition may be effective in different depressive subtypes and may have different side effects, these drugs are valuable pharmacologic probes for studying the biochemical bases of depressive disorders.