Papers by Michael Grunebaum
The International Journal of Neuropsychopharmacology, May 27, 2016
young old (Y-O): 60-74 years, old-old (O-O): >75 years. The information was obtained by interview... more young old (Y-O): 60-74 years, old-old (O-O): >75 years. The information was obtained by interviewing the subjects and caregivers. Chi-square test, ANOVA and logistic regression analysis were performed. Results: Of the 384 individuals, 56.4% (N = 214) were MA; 38.4% (N = 100), Y-O and 18.2% (N = 70) O-O. Proportion of living alone was higher in O-O group compared than other groups. The use of alcohol at the time of suicide attempt was more often in MA group compared than other groups. While interpersonal problem was major motivation in MA group, physical illness was in the elderly. Although O-O group had a higher rate of depression, they tend not to receive psychiatric evaluation. Logistic regression analyses revealed that O-O were less likely to use alcohol at the time of suicide attempt and to receive psychiatric evaluation at ER than Y-O. Conclusion: Characteristics of elderly suicide attempts are different from those of suicide attempts in middle age group. Specific therapeutic approaches or preventive strategies for the elderly may be warranted.
Neuropsychopharmacology, Jan 17, 2019
The goal of this study was to infer the effectiveness of midazolam as a comparator in preserving ... more The goal of this study was to infer the effectiveness of midazolam as a comparator in preserving the blind in ketamine studies for mood disorders through patient-level analyses of efficacy trial outcomes. In this integrative data analysis (k = 9, N = 367 patients with mood disorders), clinical outcomes were compared across four groups: ketamine (midazolam-controlled), ketamine (salinecontrolled), midazolam, and saline. Ketamine doses ranged from 0.5 to 0.54 mg/kg and midazolam doses ranged from 0.02 to 0.045 mg/kg. The baseline-to-Day 1 effect size was d = 0.7 (95% CI: 0.4-0.9) for ketamine (midazolam) versus midazolam and d = 1.8 (95% CI: 1.4-2.2) for ketamine (saline) versus saline. The effect of ketamine relative to control was larger in saline-controlled studies than in midazolam-controlled studies (t(276) = 2.32, p = 0.02). This was driven by a comparatively larger effect under midazolam than saline (t(111) = 5.40, p < 0.0001), whereas there was no difference between ketamine (midazolam) versus ketamine (saline) (t(177) = 0.65, p = 0.51). Model-estimated rates of response (with 95% CI) yielded similar results: ketamine (midazolam), 45% (34-56%); ketamine (saline), 46% (34-58%); midazolam, 18% (6-30%); saline, 1% (0-11%). The response rate for ketamine was higher than the control condition for both saline (t(353) = 7.41, p < 0.0001) and midazolam (t(353) = 4.59, p < 0.0001). Studies that used midazolam as a comparator yielded smaller effects of ketamine than those which used saline, which was accounted for by greater improvement following midazolam compared to saline.
Australian and New Zealand Journal of Psychiatry, Oct 31, 2018
Objective: To derive new criteria sets for defining manic and hypomanic episodes (and thus for de... more Objective: To derive new criteria sets for defining manic and hypomanic episodes (and thus for defining the bipolar I and II disorders), an international Task Force was assembled and termed AREDOC reflecting its role of Assessment, Revision and Evaluation of DSM and other Operational Criteria. This paper reports on the first phase of its deliberations and interim criteria recommendations. The first stage of the process consisted of reviewing Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, and recent International Classification of Diseases criteria, identifying their limitations and generating modified criteria sets for further in-depth consideration. Task Force members responded to recommendations for modifying criteria and from these the most problematic issues were identified. Results: Principal issues focussed on by Task Force members were how best to differentiate mania and hypomania, how to judge 'impairment' (both in and of itself and allowing that functioning may sometimes improve during hypomanic episodes) and concern that rejecting some criteria (e.g. an imposed duration period) might risk false-positive diagnoses of the bipolar disorders. This first-stage report summarises the clinical opinions of international experts in the diagnosis and management of the bipolar disorders, allowing readers to contemplate diagnostic parameters that may influence their clinical decisions. The findings meaningfully inform subsequent Task Force stages (involving a further commentary stage followed by an empirical study) that are expected to generate improved symptom criteria for diagnosing the bipolar I and II disorders with greater precision and to clarify whether they differ dimensionally or categorically.
Preventive Medicine, 2021
In many countries suicide rates have been trending upwards for close to twenty years-presenting a... more In many countries suicide rates have been trending upwards for close to twenty years-presenting a public health crisis. Most suicide attempts and deaths are associated with psychiatric illness, usually a depressive disorder. Subanesthetic ketamine is the only FDA-approved antidepressant that works in hours not weeks-thus potentially transforming treatment of suicidal patients. We reviewed all randomized controlled trials of the effect of ketamine on suicidal ideation to determine if ketamine rapidly reduces suicidal ideation [SI] in depressed patients and how long the benefit persists after one dose and if the route of administration or dose affects the outcome. A systematic review was conducted as per PRISMA [preferred reporting items for systematic reviews and meta-analyses] criteria. PubMed search inclusive of "ketamine" and "suicide" yielded 358 results. Papers (NÂ =Â 354) were then read by at least two authors, identifying 12 meeting eligibility requirements and eleven RCTs examining whether ketamine treatment ameliorated SI. Four of five RCTs examined racemic ketamine (0.5Â mg/kg) given intravenously and found an advantage for ketamine over control for rapid reduction in SI in acutely depressed patients. Two studies examined intranasal esketamine in depressed suicidal patients and found no advantage over saline. One study examined outcome six weeks after a single intravenous dose of ketamine and found benefit for SI sustained relative to 24Â h post-dose. Further research is warranted into: optimal dosing strategy, including number and frequency; and long-term efficacy and safety. Ultimately, it remains to be shown that ketamine's benefit for SI translates into prevention of suicidal behavior.
Molecular Psychiatry, Sep 7, 2022
Depression is disabling and highly prevalent. Intravenous (IV) ketamine displays rapid-onset anti... more Depression is disabling and highly prevalent. Intravenous (IV) ketamine displays rapid-onset antidepressant properties, but little is known regarding which patients are most likely to benefit, limiting personalized prescriptions. We identified randomized controlled trials of IV ketamine that recruited individuals with a relevant psychiatric diagnosis (e.g., unipolar or bipolar depression; posttraumatic stress disorder), included one or more control arms, did not provide any other study-administered treatment in conjunction with ketamine (although clinically prescribed concurrent treatments were allowable), and assessed outcome using either the Montgomery-Ă…sberg Depression Rating Scale or the Hamilton Rating Scale for Depression . Individual patientlevel data for at least one outcome was obtained from 17 of 25 eligible trials [pooled n = 809]. Rates of participant-level data availability across 33 moderators that were solicited from these 17 studies ranged from 10.8% to 100% (median = 55.6%). After data harmonization, moderators available in at least 40% of the dataset were tested sequentially, as well as with a data-driven, combined moderator approach. Robust main effects of ketamine on acute [~24-hours; β*(95% CI) = 0.58 (0.44, 0.72); p < 0.0001] and postacute [~7 days; β*(95% CI) = 0.38 (0.23, 0.54); p < 0.0001] depression severity were observed. Two study-level moderators emerged as significant: ketamine effects (relative to placebo) were larger in studies that required a higher degree of previous treatment resistance to federal regulatory agency-approved antidepressant medications (≥2 failed trials) for study entry; and in studies that used a crossover design. A comprehensive data-driven search for combined moderators identified statistically significant, but modest and clinically uninformative, effects (effect size r ≤ 0.29, a small-medium effect). Ketamine robustly reduces depressive symptoms in a heterogeneous range of patients, with benefit relative to placebo even greater in patients more resistant to prior medications. In this largest effort to date to apply precision medicine approaches to ketamine treatment, no clinical or demographic patient-level features were detected that could be used to guide ketamine treatment decisions.
Bipolar Disorders, Jun 1, 2008
Objective-Comorbid anxiety disorder is reported to increase suicidality in bipolar disorder. Howe... more Objective-Comorbid anxiety disorder is reported to increase suicidality in bipolar disorder. However, studies of the impact of anxiety disorders on suicidal behavior in mood disorders have shown mixed results. The presence of personality disorders, often comorbid with anxiety and bipolar disorders, may explain these inconsistencies. This study examined the impact of comorbid Cluster B personality disorder and anxiety disorder on suicidality in bipolar disorder. Methods-A total of 116 depressed bipolar patients with and without lifetime anxiety disorder were compared. Multiple regression analysis tested the association of comorbid anxiety disorder with past suicide attempts and severity of suicidal ideation, adjusting for the effect of Cluster B personality disorder. The specific effect of panic disorder was also explored. Results-Bipolar patients with and without anxiety disorders did not differ in the rate of past suicide attempt. Suicidal ideation was less severe in those with anxiety disorders. In multiple regression analysis, anxiety disorder was not associated with past suicide attempts or with the severity of suicidal ideation, whereas Cluster B personality disorder was associated with both. The results were comparable when comorbid panic disorder was examined. Conclusions-Comorbid Cluster B personality disorder appears to exert a stronger influence on suicidality than comorbid anxiety disorder in persons with bipolar disorder. Assessment of suicide risk in patients with bipolar disorder should include evaluation and treatment of Cluster B psychopathology.
Journal of Affective Disorders, 2009
Background-Assessment of suicide plans is standard in acute psychiatric care, but there is a limi... more Background-Assessment of suicide plans is standard in acute psychiatric care, but there is a limited evidence base to guide this routine clinical practice. The purpose of this study was to investigate clinical correlates of suicide planning in depressed patients. Methods-151 patients with major depressive disorder and a lifetime history of suicide attempt were studied. Subjects received a comprehensive evaluation including structured diagnostic interview for Axis I and II disorders, current symptoms, impulsivity, and systematic assessment of suicide planning prior to the most recent suicide attempt. Results-Seriousness of suicide attempt planning correlated with lethality of suicidal acts. Comorbid anxiety disorder and anxiety correlated with less suicide planning. Specifically, this negative correlation was with comorbid panic disorder. Planning did not correlate with severity of depression or aggressive/impulsive traits. Limitations-Cross-sectional design, retrospective recall of suicide planning data, limited applicability to completed suicide or other psychiatric disorders. Conclusions-In major depression, comorbid panic disorder appears protective against more carefully planned, higher lethality suicide attempts. Surprisingly, severity of depression and aggressive impulsive traits do not predict planning or lethality of suicide attempts. We have previously reported that anxiety severity protects against the probability of a suicide attempt and now extend that observation to show there is protection against lethality of a suicide attempt. Treatment of anxiety without directly treating major depression may place patients at greater risk of suicidal behavior.
Journal of Psychiatric Research, Oct 1, 2014
Major depressive disorder (MDD) is associated with low levels of omega-3 polyunsaturated fatty ac... more Major depressive disorder (MDD) is associated with low levels of omega-3 polyunsaturated fatty acids (PUFAs), holding promise for new perspectives on disease etiology and treatment targets. As aggressive and impulsive behaviors are associated with low omega-3 PUFA levels in some clinical contexts, we investigated plasma PUFA relationships with trait aggression and impulsivity in patients with MDD. Medication-free MDD patients (n=48) and healthy volunteers (HV, n=35) were assessed with the Brown-Goodwin Aggression Inventory. A subset (MDD, n=39; HV, n=33)
Archives of Suicide Research, 2007
There is some evidence for an association between Cluster C Personality Disorders (CCPD) and suic... more There is some evidence for an association between Cluster C Personality Disorders (CCPD) and suicidal behavior. We compared depressed inpatients with and without CCPD in terms of suicidal behavior and associated psychopathology. Cluster A or B personality disorder co-morbidity were exclusion criteria for both groups (cases and controls). Depressed inpatients with "pure" CCPD had higher levels of suicidal ideation but not more previous suicide attempts compared with patients without CCPD. Greater suicidal ideation in depressed patients with CCPD in our study was associated with more hostility. Future studies examining the relationship between suicidal ideation and hostility in CCPD may clarify whether treatment focused on hostility might be of use for decreasing suicidal ideation in depressed patients with CCPD (Spitzer, Williams, Gibbon et al., 1990).
Journal of Affective Disorders, May 1, 2009
Background-We aimed to examine the adequacy of antidepressant treatment and compliance with treat... more Background-We aimed to examine the adequacy of antidepressant treatment and compliance with treatment in bipolar patients with and without alcohol use disorders (AUD). We hypothesize that the adequacy of antidepressant treatment and the compliance with treatment for those with AUD are lower than for those without AUD. Methods-Subjects were 97 patients with current bipolar major depressive episode, 39 (40.2%) with lifetime history of AUD and 58 (59.8%) without AUD. Adequacy of antidepressant medication treatment in the 3 previous months was assessed using the Antidepressant Treatment History Form. Compliance rates were estimated. Results-Rates of inadequate treatment were high in all patients. Bipolar patients with AUD (74.3%) showed higher rates of inadequate antidepressant treatment than those without AUD (67.3%). The proportion of intensive treatment was higher in bipolars without AUD (15.5%) than in those with AUD (2.6%). Median compliance was similar in bipolars with and without AUD. Limitations-We lack serum medication levels to assess the compliance. We do not have data to address the possibility that the presence of AUD adversely affected prescribing practices. Conclusions-Bipolars with AUD had lower rates of adequate treatment than those without AUD, but the two groups were not different in terms of self-reported treatment adherence. The finding that bipolar patients with or without comorbid AUD did not receive adequate treatment is of considerable clinical relevance. It raises the question as to whether inadequate treatment of depression contributes to the high rates of morbidity, and attempted and completed suicides in bipolar patient populations.
The Journal of Clinical Psychiatry, Apr 15, 2006
ABSTRACT
Crisis-the Journal of Crisis Intervention and Suicide Prevention, Sep 1, 2017
There is compelling evidence that suicide attempts are among the strongest predictors of suicide ... more There is compelling evidence that suicide attempts are among the strongest predictors of suicide and future suicide attempts. This study aimed to examine psychopathology in multiple-suicide attempters. We compared the demographic and clinical features of three groups: depressed patients without a history of suicide attempts (non-attempters), depressed patients with a history of one to three suicide attempts (attempters), and depressed patients with a history of four or more suicide attempts (multiple attempters). We found that attempters and multiple attempters had higher levels of depression, hopelessness, aggression, hostility, and impulsivity and were more likely to have borderline personality disorder and family history of major depression or alcohol use disorder compared with non-attempters, but did not differ between each other on these measures. Multiple attempters had greater suicidal ideation at study entry and were more likely to have family history of suicide attempt compared with attempters. Importantly, multiple attempters had greater suicide intent at the time of the most medically serious suicide attempt and more serious medical consequences during their most medically serious suicide attempt compared with attempters. The cross-sectional design of the study. Our data suggest that multiple-suicide attempters require careful evaluation as their behavior can have serious medical consequences.
Neuropsychopharmacology, May 16, 2003
Major depression and alcoholism are often comorbid, resulting in more impairment and more suicida... more Major depression and alcoholism are often comorbid, resulting in more impairment and more suicidal behavior compared with either diagnosis alone. This study compared clinical features and cerebrospinal fluid (CSF) monoamine metabolites in depressed subjects with and without a history of alcoholism and healthy volunteers. We hypothesized that depressed subjects with a history of alcoholism would be more aggressive, impulsive, and suicidal than depressed subjects without a history of alcoholism, and would have lower CSF monoamine metabolite levels. We compared 63 subjects with a current major depressive episode (MDE) and a history of alcoholism, 72 subjects with a current MDE but without a history of alcoholism, and 22 healthy volunteers. Participants with a history of alcoholism were in remission for at least 6 months. All subjects were free from prescribed medications known to affect brain serotonin, dopamine, or norepinephrine systems for a minimum of 14 days. Depressive symptoms, lifetime aggression, impulsivity, Axis II disorders, and suicidal behavior were assessed. CSF was sampled and homovanillic acid (HVA), 5-hydroxyindolacetic acid (5-HIAA), and 3-methoxy-4hydroxyphenylglycol (MHPG) were assayed by high-performance lipid chromatography with electrochemical detection. Depressed subjects with a history of alcoholism did not differ from depressed subjects without a history of alcoholism in current severity of depressive symptoms, or in past suicidal behavior. Depressed subjects with a history of alcoholism had lower CSF HVA levels, and higher lifetime aggression and current suicide ideation scale scores and were more likely to be tobacco smokers compared with depressed subjects without a history of alcoholism. Low HVA was present after adjustment for sex, aggression and depression scores, cigarette smoking, antisocial and borderline personality disorders, psychomotor retardation, and delusions. Controls had CSF HVA levels intermediate between the two depressed groups. We found no group difference in CSF 5-HIAA and MHPG levels. In individuals with current MDE, those with a history of comorbid alcoholism had lower CSF HVA levels compared with those without a history of alcoholism. Low CSF HVA suggests that impaired dopaminergic activity is associated with a history of alcoholism in persons with current MDE.
Psychiatry Research-neuroimaging, Feb 1, 2015
Neuropsychological dysfunction is associated with risk for suicidal behavior, but it is unknown i... more Neuropsychological dysfunction is associated with risk for suicidal behavior, but it is unknown if antidepressant medication treatment is effective in reducing this dysfunction, or if specific medications might be more beneficial. A comprehensive neuropsychological battery was administered at baseline and after eight weeks of treatment within a randomized, double-blind clinical trial comparing paroxetine and bupropion in study of patients with DSM-IV major depressive disorder and either past suicide attempt or current suicidal thoughts. Change in neurocognitive performance was compared between assessments and between medication groups. Treatment effects on Hamilton Depression Rating Scale and Scale for Suicidal Ideation were compared with neurocognitive improvement. Neurocognitive functioning improved after treatment in all patients, without clear advantage for either medication. Improvement in memory performance was associated with a reduction in suicidal ideation independent of the improvement of depression severity. Overall, antidepressant medication improved neurocognitive performance in patients with major depression and suicide risk. Reduced suicidal ideation was best predicted by a combination of the independent improvements in both depression symptomatology and verbal memory. Targeted treatment of neurocognitive dysfunction in these patients may augment standard medication treatment for reducing suicidal behavior risk.
Journal of Nervous and Mental Disease, Dec 1, 2006
Most previous studies compared suicidal behavior in subjects with and without a history of childh... more Most previous studies compared suicidal behavior in subjects with and without a history of childhood abuse, whereas less attention was paid to the comparison of suicide attempters and nonattempters among subjects reporting childhood abuse. To identify risk and protective factors against suicidal behavior, we compared suicide attempters with nonattempters among the sample of 119 depressed inpatients who reported childhood abuse. Compared with nonattempters, suicide attempters were younger, had more self-rated depression severity and suicidal ideation, higher trait aggression and more cluster B personality disorder comorbidity, less coping potential, and fewer moral objections to suicide (MOS)/religious beliefs. Logistic regression showed that more severe suicidal ideation and fewer MOS/religious beliefs were associated with suicidal acts in subjects with reported childhood abuse. Furthermore, suicidal ideation and MOS/religious beliefs were significantly inversely correlated. The results of this clinical study add support to previous reports that religious/spiritual coping could serve as an additional resource in prevention of suicidal behavior for subjects with reported childhood abuse.
American Journal of Psychiatry, Oct 1, 2002
Clinical Neuroscience Research, Nov 1, 2001
Research issues associated with outcomes of suicidal behavior include: the appropriate length of ... more Research issues associated with outcomes of suicidal behavior include: the appropriate length of time to follow subjects is at least two years, psychiatric controls without a history of suicide attempt are a recommended comparison group, quantitation of traits such as aggression or impulsivity is desirable. Clinical issues include the following: the diathesis for suicide is a trait, the most universal risk factor across groups is the presence of depression, yet under-treatment, such as inadequate dosing of antidepressants and high rates of drop-out from psychotherapy, is a major problem. Other issues include that treatment must take a lifelong perspective, there is an ongoing need for psychoeducation of practitioners and the public, outreach to institutions such as schools, hospitals and jails is needed, when a child or adolescent exhibits suicidal behavior, parents should be screened for psychiatric illness, there is an urgent need to remedy barriers to treatment including insurance coverage obstacles, long wait-lists, and fragmentation of mental healthcare. Improvements should include a focus on step-down treatments and the integration of primary care and mental healthcare. Establishing a national registry of serious suicidal behavior to aid research, and clinical trials of treatments for suicidal behavior is important. Subpopulations for study include children, adolescents, the elderly, institutionalized persons, community samples (as distinct from clinical samples), persons with a family history of suicide (for genetic linkage studies), attempters versus completers, single versus multiple attempters and persons who drop out of treatment.
European Psychiatry, 2018
Suicidal behavior is highly prevalent among patients with mood disorders [1]. The rate of suicide... more Suicidal behavior is highly prevalent among patients with mood disorders [1]. The rate of suicide in such patients can be as high as 15-20% [2]. Suicide attempts are also prevalent in this population, with studies showing that up to 50% of patients with bipolar disorder (BD) and 30-40% of patients with major depressive disorder (MDD) have lifetime history of suicide attempts [3-5]. Bipolar disorder and MDD share certain risk factors for suicide attempts, such as previous suicide attempts, greater severity of depression, comorbidity with alcohol or substance use, and comorbidity with anxiety disorders [6-8]. Anxiety disorders have been linked to suicidal behavior in the general population and in individuals with other psychiatric disorders. In a recent meta-analysis [9], patients with anxiety disorders were more likely to report suicidal ideation (OR: 2.89, 95% CI: 2.09-4.00), to have attempted suicide (OR: 2.47, 95% CI: 1.96-3.10), and to have died by suicide (OR: 3.34, 95% CI: 2.13-5.25) in comparison with patients without anxiety disorders, even after adjusting for comorbid depression. There are few prospective studies investigating the role of lifetime comorbid anxiety disorders in future suicide attempts. These studies have produced conflicting results. A prospective study with a 3-year follow-up period, showed that the risk of suicide attempt was four times greater among patients with anxiety disorders and comorbid mood disorders than among those with anxiety disorders only (OR: 4.15, 95% CI: 1.34-12.9) and among those with mood disorders only (OR: 2.44, 95% CI:
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Papers by Michael Grunebaum