Slower perception of time in depressed and suicidal patients.

Effective suicide prevention is hindered by a limited understanding of the natural progression and neurobiology of the suicidal process. Our objective was to characterize the duration of the suicidal process and its relation to possible determinants: time judgment and cognitive impulsivity. In four groups of adults of both sexes including recent suicide attempters (n = 57), suicidal ideators (n = 131), non-suicidal depressed controls (n = 51) and healthy controls (n = 48) we examined time estimation and production, impulsivity and other cognitive variables. Duration of the suicidal process was recorded in suicide attempters. The suicide process duration, suicide contemplation and action intervals, had a bimodal distribution, ∼40% of attempters took less than 5 min from decision to attempt. Time slowing correlated negatively with the suicidal action interval (time from the decision to kill oneself to suicide attempt) (p = .003). Individuals with suicide contemplation interval shorter than three hours showed increased time slowing, measured as shorter time production at 35 s (p = .011) and 43 s (p = .036). Delay discounting for rewards correlated with time estimation at 25 min (p = .02) and 90 s (p = .01). Time slowing correlated positively with suicidal ideation severity, independently of depression severity (p < .001). Perception of time slowing may influence both the intensity and the duration of the suicidal process. Time slowing may initially be triggered by intense psychological pain, then worsen the perception of inescapability in suicidal patients.

Mangomoments - preconditions and impact on patients and families, healthcare professionals and organisations: a multi-method study in Flemish hospitals.

OBJECTIVE: Understanding how small unexpected acts or gestures by healthcare professionals, known as Mangomoments, are translated into practice, what their preconditions are and what their impact is on patients and families, healthcare professionals and organisations. DESIGN: A multi-method design was used based on four phases: (1) A (media)campaign to collect Mangomoment stories (n=1045), of which 94% (n=983) were defined as Mangomoments; (2) Semi-structured interviews (n=120); (3) Focus group interviews (n=3); and (4) A consensus meeting. SETTING: Respondents from a hospital and primary care setting. PARTICIPANTS: Patients, family, healthcare professionals, managers, researchers and a policymaker participated. RESULTS: Mangomoments are mainly classified in the dimensions 'Respect for values, preferences and needs' and 'Emotional support'. Differences in importance of the dimensions were found between healthcare professionals, oncological patients and family and non-oncological patients and family. The results of the interviews, focus groups and consensus meeting were visualised by the Mangomoment model. It identifies several preconditions on the level of patients, healthcare professionals and leadership. For each of these preconditions a catalyst was identified to increase the prevalence of Mangomoments. In general, Mangomoments improved the patient and family experience and facilitated adherence to therapy and led to a positive perception on the healing process. Positive effects for professionals include personal accomplishment and anti-burnout, joy in work and a positive team atmosphere. This led to positive resonance by a relationship of trust between the patient and the healthcare professionals, feelings of tolerance during negative experiences and open communication and a safe climate. Overall, patients and healthcare workers concluded that Mangomoments led to loyalty to the healthcare organisation. CONCLUSION: Mangomoments do not only have a positive impact on patient and family but also on the healthcare professional. Leadership should shape several preconditions and catalysts which can lead to positive resonance and loyalty of patients and professionals.

Buprenorphine use for pain and suicidal ideation in severely suicidal patients.

OBJECTIVE: Chronic pain is frequently comorbid with opioid abuse and severe depression, a combination that greatly compounds suicide risk. In addition to the therapeutic value of buprenorphine in addiction and analgesia, growing evidence suggests potential use as an antidepressant. Data supporting buprenorphine antisuicidal properties are scarce. We aim to contribute to the discussion of buprenorphine antisuicidal potential in patients with significant psychiatric and medical comorbidity. METHODS: We performed a chart review of suicidal adult depressed patients with comorbid chronic pain and opioid use disorder who received off-label buprenorphine in outpatient and inpatient settings in a university hospital between 2013 and 2016. RESULTS: Four of the patients had an early positive response. However, only three continue to adhere to treatment for six months or longer. CONCLUSIONS: More severe opioid use disorder seems to more negatively influence clinical outcome, independently of cluster b personality traits. Identification of patients who could benefit from buprenorphine will require further studies.

The neural correlates of low social integration as a risk factor for suicide.

Low social integration is commonly described in acutely suicidal individuals. Neural mechanisms underlying low social integration are poorly understood in depressed and suicidal patients. We sought to characterize the neural response to low social integration in acutely suicidal patients. Adult depressed patients within 3 days of a suicide attempt (n = 10), depressed patients with suicidal ideation (n = 9), non-suicidal depressed patients (n = 15), and healthy controls (N = 18) were administered the Cyberball Game while undergoing functional magnetic resonance imaging. We used complementary functional connectivity and region of interest data analysis approaches. There were no group differences in functional connectivity within neural network involving the pain matrix, nor in insula neural activity or the insula during either social inclusion. Superior anterior insula activity exhibited an inverted U-shaped curve across the suicide risk spectrum during social inclusion. Superior insula activity during social inclusion correlated with depression severity and psychological pain. Dorsal anterior cingulate cortex activity during social exclusion correlated with physical pain severity. Neural responses in the anterior insula significantly correlated with depression severity and with psychological pain during social inclusion, whereas dACC activity significantly correlated with physical pain during social exclusion. Recent suicidal behavior seems associated with a distinct neural response to social exclusion independently of presence of depression or suicidal thoughts.

Examination of pain threshold and neuropeptides in patients with acute suicide risk.

INTRODUCTION: One of the main challenges in suicide prevention is the limited understanding of the biological mechanisms underlying suicide. Recent findings suggest impairments in pain processing in acutely suicidal patients. However, little is known about the biological factors that may drive these discrete physiological abnormalities. In this study, we examined plasma peptides involved in analgesic and inflammatory responses and physical pain threshold in acutely suicidal patients. METHODS: Thirty-seven depressed patients of both sexes hospitalized for severe suicidal ideation or a recent suicide attempt were characterized clinically including history of suicidal ideation and behavior. Psychological and physical pain, and pressure pain threshold was also measured. Plasma levels of ß-endorphin, neurotensin, agouti-related protein (AgRP), C-reactive protein (CRP), adrenocorticotropic hormone (ACTH), and brain-derived neurotrophic factor (BDNF) were run in Milliplex multiplex assays. RESULTS: The number of lifetime suicide attempts was positively correlated with ß-endorphin (r = 0.702; p = 0.007), and neurotensin (r = 0.728, p = 0.007) plasma levels. Higher pain threshold was measured in the suicide attempt group as compared to the suicidal ideation group. Pain threshold was strongly and negatively associated with CRP plasma levels (r = -0.548; p < 0.001). In patients reporting chronic pain, lower AgRP levels and lower pain threshold were observed (t = 4.472; p = 0.001). CONCLUSION: Our results suggest that abnormalities in the opioid and neurotensin systems may underlie the increase in pain threshold found in suicide attempters, and possibly risk for suicidal behavior. Targeting pain circuits and systems may provide therapeutic mechanisms for suicide prevention.

A probe in the connection between inflammation, cognition and suicide.

BACKGROUND: Increased inflammation is linked to suicide risk. However, it is unclear whether increased inflammation drives suicidal crises or is a trait associated with lifetime suicidal behavior. Limited data exist on the sources of increased inflammation observed in suicidal patients and on its downstream effects. AIMS: To examine factors associated with inflammation and with suicidal ideation severity in acutely suicidal depressed patients. METHODS: Fifty-two adult depressed patients of both sexes hospitalized for severe suicidal ideation were characterized for suicidality, depression, anxiety, medical comorbidity, psychological and physical pain, impulsivity, verbal fluency, C-reactive protein (CRP) and interleukin (IL) 6. Two generalized linear models were performed with either CRP or suicidal ideation severity as dependent variables. RESULTS: CRP levels were positively associated with age, body mass index (BMI), IL6, current physical pain and number of lifetime suicide attempts. Suicidal ideation severity was not significantly correlated with either CRP or IL6. Suicidal ideation severity was positively associated with female sex, presence of an anxiety disorder, current physical pain, number of lifetime suicide attempts and with delay discounting for medium and large losses. CONCLUSIONS: Increased inflammation is not associated with acute suicidal risk, but seems to represent a trait associated with lifetime suicidal behavior.

Association Study of Genotype by Depressive Response during Tryptophan Depletion in Subjects Recovered from Major Depression.

PURPOSE: The brief and reversible mood response to acute tryptophan (TRP) depletion (ATD) is being studied as a trait marker in subjects considered at risk for major depression (MD). PROCEDURES: ATD was administered to 64 subjects (54 European-Americans, and10 from other races) with personal and family history of MD. They were in remission and had been medication-free for at least three months. Subjects received an active and sham condition in a random assignment, double-blind crossover design. They were genotyped for serotonin-related candidate genes, and mood response was quantified with the Hamilton Depression Rating Scale (HDRS). Data were analyzed using Poisson regression with repeated measures and latent trajectory models. RESULTS: Compared to the sham control, active ATD caused modest depressive changes showing significant main effects of test condition (χ2=5.14, df=1, p=0.023) and time (χ2=12.22, df=3, p=0.007), but no significant interaction of time and test condition. Latent trajectory analysis revealed two groups, identified as depletion responders and non-responders. Those with the HTR2A rs6313 CC genotype had significantly higher HDRS scores during ATD (χ2=11.72, df=1, p=.0006). CONCLUSIONS AND MESSAGE: ATD may help the identification of biological subtypes of MD. These data are consistent with imaging reports implicating 5-HT2A receptor function in ATD phenotypes.

CSF neurochemicals during tryptophan depletion in individuals with remitted depression and healthy controls.

The purpose of this study was to examine the differential effects of acute tryptophan (TRP) depletion vs. sham condition on plasma, cerebrospinal fluid (CSF) biochemical parameters, and mood in the following three subject groups: (1) nine antidepressant-free individuals with remitted depression, (2) eight paroxetine-treated individuals with recently remitted depression, and (3) seven healthy controls. Plasma TRP decreased during TRP depletion and increased during sham condition (p<.01). CSF TRP and 5-hydroxyindoleacetic acid were lower during TRP depletion than sham condition (p<.01 each). During TRP depletion, CSF TRP correlated significantly with the plasma sum of large neutral amino acids (SigmaLNAA) (R=-.52, p=.01), but did not significantly correlate with plasma TRP (R=.15, p=.52). The correlation between CSF TRP and ratio of TRP to SigmaLNAA was R=.41 and p=.06 during TRP depletion, and R=-.44 and p=.04 during sham condition. A negative correlation trend was observed between CSF-TRP levels and peak Hamilton Depression Rating Scale scores during TRP depletion in patients recovered from depression (R=-.45, p=.07), but not in healthy controls (R=-.01, p=.98). CSF neuropeptide Y was higher during TRP depletion than sham condition (t=1.75, p<.10). These results illustrate the importance of assessing plasma SigmaLNAA when using the TRP depletion paradigm. The use of a single CSF sampling technique although practical may result in data acquisition limitations.

Alteration of frontal EEG asymmetry during tryptophan depletion predicts future depression.

BACKGROUND: Tryptophan depletion (TD) reduces brain serotonin and may induce acute depressive symptomatology, especially among those with a history of Major Depression. Depressive response to TD among euthymic patients with a history of depression also predicts future depression. Better prediction might result by assessing a putative endophenotype for depressive risk, frontal electroencephalographic (EEG) asymmetry, in the context of TD. METHOD: Nine euthymic history-positive participants and nine controls were administered TD. Symptomatic and EEG frontal asymmetry data were collected for 6 h following TD, and clinical status was followed for the next 12 months. RESULTS: The magnitude of TD-induced change in frontal EEG asymmetry significantly predicted the development of depression during the ensuing six to twelve months, and with greater sensitivity than symptomatic response. LIMITATIONS: The results are tempered by the small sample size. CONCLUSIONS: Despite the limited sample size, these preliminary results suggest that TD-induced changes in frontal EEG asymmetry may provide a more sensitive indicator of risk for imminent depression than symptomatic response to TD.

The relationship of personality traits to substance abuse in patients with bipolar disorder.

PURPOSE: The aim of this study is to determine if personality traits contribute to the likelihood of substance abuse in Bipolar Disorder (BD). SUBJECTS/MATERIALS AND METHODS: Fifty-nine patients meeting DSM-IV criteria for BD: 20 without any history of Substance Related Disorder (SRD), 21 with a lifetime history of SRD but without current SRD, and 18 with current SRD. Patients filled out the TCI, the differences were analyzed by ANOVA and the likelihood was obtained by Multinomial Logistic Regression. RESULTS: Only Novelty Seeking (NS) is statistically different between the groups. Patients with BD with current SRD have higher rates in NS than those with past SRD, and those without a history of SRD. NS was confirmed as a predicting variable, both to current SRD (OR [CI 95%]=1.039/1.351; p=0.011) and past SRD (OR [CI 95%]=1.004/1.277; p=0.042) on patients with BD. DISCUSSION: The results shown would appear to confirm the relationship of NS with the SRD, so long as there is no clear evidence that indicates the association of NS with BD. CONCLUSIONS: There appears a greater predisposition to develop SRD in those patients with a higher degree of NS. The use of the Cloninger's TCI could be used in BD to determine the risk of developing an SRD. Early detection might help improve prognosis.

Sex differences in depressive response during monoamine depletions in remitted depressive subjects.

OBJECTIVE: Although sex differences in the prevalence of depression are well known, the effects of sex on the underlying mechanisms of illness and on antidepressant action remain less clear. Tryptophan depletion and catecholamine depletion (via alpha-methylparatyrosine [AMPT] administration) are broadly utilized methods for studying the effects of the safe and transient reduction of serotonin and catecholamine neuro-transmission, respectively. The present study assessed the effects of sex on the mood response during acute monoamine depletion. METHOD: Data on Hamilton Rating Scale for Depression (HAM-D) scores during depletion tests were analyzed retrospectively in 59 subjects (41 women, 18 men) who underwent tryptophan depletion and 39 subjects (25 women, 14 men) who underwent catecholamine depletion. All subjects were in remission from a DSM-IV-defined major depressive episode. Data reviewed included subjects enrolled between November 1993 and November 1997. RESULTS: Significant increases in HAM-D scores were observed in response to both depletion procedures, with a similar magnitude of change. Analysis of variance with repeated measures of HAM-D scores revealed a significant main effect of time for tryptophan depletion (F = 7.31, df = 3, p < .01) and for catecholamine depletion (F = 9.61, df = 4, p < .01). Time-by-sex interaction was significant for tryptophan depletion (F = 4.04, df = 3, p = .01), but not for catecholamine depletion (F = 0.75, df = 4, p = .57). Depressive symptoms were significantly greater in women during tryptophan depletion (t test p < .01), while no significant sex differences were found during catecholamine depletion. CONCLUSIONS: These findings suggest that the effect of sex in depressive vulnerability may be related to differential sex effects in monoaminergic function.

Monoamine depletion studies: implications for antidepressant discontinuation syndrome.

The likelihood of a connection between serotonin reuptake inhibitor (SRI) discontinuation and an acute reduction in synaptic serotonin (5-HT) has ignited interest in the similarities between SRI discontinuation syndrome and the symptoms observed after acute tryptophan depletion, which reduces synaptic 5-HT levels. An open question is whether these 2 phenomena have shared characteristics because of a similar underlying mechanism. The evidence in support of a similar underlying mechanism includes the observation that comparable proportions of SRI-treated patients experience depressive symptoms following tryptophan depletion and SRI discontinuation. Furthermore, the proportion of people who have emotional changes with rapid antidepressant discontinuation may be parallel to the proportion of people who experience those changes with rapid tryptophan depletion.

Antidepressant discontinuation syndrome: consensus panel recommendations for clinical management and additional research.

OBJECTIVE: Currently, no evidence-based guidelines exist for the management of serotonin reuptake inhibitor (SRI) discontinuation syndrome. This article summarizes recommendations with respect to future research as well as clinical management recommendations for SRI discontinuation syndrome. PARTICIPANTS: In April 2004, a panel of physicians convened in New York City to discuss recommendations for clinical management of and additional research on SRI discontinuation syndrome. EVIDENCE: Previous guidance for management of SRI discontinuation syndrome was proposed in 1997 in a consensus meeting also chaired by Alan F. Schatzberg. A literature search of the PubMed database was conducted to identify articles on SRI discontinuation syndrome that have been published since 1997. CONSENSUS PROCESS: The 2004 panel reviewed important preclinical and clinical studies, discussed prospective investigation of this syndrome in clinical trials, and suggested the establishment of a research network to collect data in naturalistic settings. The panel also reviewed the management recommendations published in 1997 and subsequently updated the recommendations, taking into account the latest clinical data as well as the personal experience of its members with patients. CONCLUSIONS: Additional preclinical and clinical studies are necessary to further elucidate the underlying biological mechanisms of SRI discontinuation syndrome and to identify the patient populations and agents that are most affected by this phenomenon. Management strategies include gradual tapering of doses and should emphasize clinical monitoring and patient education.

Safety, tolerability, and efficacy of psilocybin in 9 patients with obsessive-compulsive disorder.

BACKGROUND: Anecdotal reports suggest that psychedelic agents may relieve symptoms of obsessive-compulsive disorder (OCD). This modified double-blind study investigated the safety, tolerability, and clinical effects of psilocybin, a potent 5-HT(1A) and 5-HT(2A/2C) agonist, in patients with OCD. METHOD: Nine subjects with DSM-IV-defined OCD and no other current major psychiatric disorder participated in up to 4 single-dose exposures to psilocybin in doses ranging from sub-hallucinogenic to frankly hallucinogenic. Low (100 microg/kg), medium (200 microg/kg), and high (300 microg/kg) doses were assigned in that order, and a very low dose (25 microg/kg) was inserted randomly and in double-blind fashion at any time after the first dose. Testing days were separated by at least 1 week. Each session was conducted over an 8-hour period in a controlled environment in an outpatient clinic; subjects were then transferred to a psychiatric inpatient unit for overnight observation. The Yale-Brown Obsessive Compulsive Scale (YBOCS) and a visual analog scale measuring overall obsessive-compulsive symptom severity were administered at 0, 4, 8, and 24 hours post-ingestion. The Hallucinogen Rating Scale was administered at 8 hours, and vital signs were recorded at 0, 1, 4, 8, and 24 hours after ingestion. The study was conducted from November 2001 to November 2004. RESULTS: Nine subjects were administered a total of 29 psilocybin doses. One subject experienced transient hypertension without relation to anxiety or somatic symptoms, but no other significant adverse effects were observed. Marked decreases in OCD symptoms of variable degrees were observed in all subjects during 1 or more of the testing sessions (23%-100% decrease in YBOCS score). Repeated-measures analysis of variance for all YBOCS values revealed a significant main effect of time on Wilks lambda (F = 9.86, df = 3,3; p = .046), but no significant effect of dose (F = 2.25, df = 3,3; p = .261) or interaction of time and dose (F = 0.923, df = 9,45; p = .515). Improvement generally lasted past the 24-hour timepoint. CONCLUSIONS: In a controlled clinical environment, psilocybin was safely used in subjects with OCD and was associated with acute reductions in core OCD symptoms in several subjects.

Serotonin noradrenaline reuptake inhibitors: New hope for the treatment of chronic pain.

Depression and painful symptoms occur frequently together. Over 75% of depressed patients report painful symptoms such as headache, stomach pain, neck and back pain as well as non-specific generalized pain. In addition, World Health Organization data have shown that primary care patients with chronic pain have a four fold greater risk of becoming depressed than pain-free patients. Increasingly, pain is considered as an integral symptom of depression and there evidence to suggest that pain and depression may arise from a common neurobiological dysfunction. Serotonergic cell bodies, in the raphe nucleus, and noradrenergic cell bodies in the locus coeruleus send projections to various parts of the brain, where they are involved in the control of mood, movement, cognitive functioning and emotions. In addition both serotonergic and noradrenergic neurons project to the spinal cord. These descending pathways serve to inhibit input from the intestines, skeletal muscles and other sensory inputs. Usually, these inhibitory effects are modest, but in times of stress, in the interest of the survival of the individual, they can completely inhibit the input from painful stimuli. A dysfunction of the serotonergic and noradrenergic neurons can thus affect both the ascending and descending pathways resulting in the psychological symptoms of depression and somatic pain symptoms such as chronic pain, fibromyalgia, non-cardiac chest pain, or irritable bowel syndrome. In view of this, it is not surprising that tricyclic antidepressants have been a standard treatment of chronic pain for many years. In contrast and in spite of their improved tolerance, selective serotonin reuptake inhibitors do not appear to be particularly effective in the treatment of pain. Recently, a number of open and controlled trials with selective serotonin and noradrenaline reuptake inhibitors such as venlafaxine, milnacipran and duloxetine, suggest that these compounds may be more effective in relieving pain than selective inhibitors of serotonin reuptake. Wherever valid comparisons have been made the newer dual action drugs appear to be as effective as the tricyclic and considerably better tolerated. Dual action antidepressants may thus soon become the new standard treatment of chronic pain whether it is associated with depression or not. In addition, these agents may also have a role in modulating neurogenesis and other neuroplastic changes in the central nervous system, thereby leading to more complete recovery in patients suffering from the symptoms of depression or chronic pain.

Sexual functioning assessed in 4 double-blind placebo- and paroxetine-controlled trials of duloxetine for major depressive disorder.

OBJECTIVE: The onset or worsening of sexual dysfunction is a common treatment-emergent side effect of antidepressant medications. Post hoc analyses of pooled data from placebo-controlled studies were utilized to assess sexual functioning in patients receiving duloxetine or paroxetine. METHOD: Acute-phase data were obtained from four 8-week, double-blind, placebo- and paroxetine-controlled trials of similar design in which patients meeting DSM-IV criteria for major depressive disorder were randomly assigned to receive placebo (N = 371), duloxetine (40-120 mg/day; N = 736), or paroxetine (20 mg/day; N = 359). Pooling of data from these studies was anticipated during study design. This represented all available data from duloxetine studies in which the Arizona Sexual Experience Scale (ASEX) was administered both at baseline and endpoint. Long-term data were available from extension phases in 2 of these trials in which acute treatment responders received placebo (N = 129), duloxetine (80-120 mg/day; N = 297), or paroxetine (20 mg/day; N = 140) for an additional 26 weeks. Data were collected between March 2000 and July 2002. RESULTS: The incidence of acute treatment-emergent sexual dysfunction was significantly lower among duloxetine-treated patients compared with those receiving paroxetine (p = .015), although both rates were significantly higher than placebo (p = .007 and p < .001 for duloxetine and paroxetine, respectively). Treatment group differences in the incidence of treatment-emergent dysfunction did not vary significantly by gender. In female patients, acute treatment-emergent sexual dysfunction was significantly lower in the duloxetine treatment group compared with the paroxetine treatment group (p = .032), with both rates being significantly higher than placebo (p = .049 and p < .001 for duloxetine and paroxetine, respectively). In the somewhat smaller group of male patients, acute treatment-emergent dysfunction did not differ significantly between duloxetine and placebo treatment groups, but the incidence was significantly higher in paroxetine-treated male patients compared with male placebo patients (p = .012). The long-term incidence of treatment-emergent dysfunction did not differ significantly between duloxetine-, paroxetine-, and placebo-treated patients. CONCLUSION: In this analysis of pooled data, patients receiving duloxetine (40-120 mg/day) or paroxetine (20 mg/day) had a significantly higher incidence of acute treatment-emergent sexual dysfunction when compared with placebo patients. However, the incidence of acute treatment-emergent dysfunction for duloxetine was significantly lower than that observed for paroxetine.

Immediate switching of antidepressant therapy: results from a clinical trial of duloxetine.

BACKGROUND: Approximately half of all treated depressed patients fail to show adequate response to their initially prescribed antidepressant medication. Switching to another medication represents one possible next-step approach for nonresponsive or partially responsive patients. However, specific techniques for switching between antidepressants have not been well studied. We examined the efficacy and tolerability associated with a switch from a selective serotonin reuptake inhibitor (SSRI) or venlafaxine to duloxetine. METHODS: All patients met criteria for major depressive disorder as defined in DSM-IV. Patients (N = 88) exhibiting suboptimal response or poor tolerability to their current antidepressant medication (citalopram or=10% of patients in both treatment groups were nausea, headache, dry mouth, insomnia, and diarrhea. Patients switched to duloxetine reported significantly lower rates of nausea and fatigue compared with patients initiating duloxetine. CONCLUSIONS: In this study, the efficacy of duloxetine in switched patients was comparable to that observed in patients initiating duloxetine therapy. Immediate switching from an SSRI or venlafaxine to duloxetine (60 mg QD) was well tolerated.