Alexander McGirr

A systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials of ketamine in the rapid treatment of major depressive episodes

BACKGROUND There is growing interest in glutamatergic agents in depression, particularly ketamine, a glutamate N-methyl-d-aspartate (NMDA) receptor antagonist. We aimed to assess the efficacy of ketamine in major depressive episodes. METHOD We searched EMBASE, PsycINFO, CENTRAL, and Medline from 1962 to January 2014 to identify double-blind, randomized controlled trials with allocation concealment evaluating ketamine in major depressive episodes. Clinical remission, response and depressive symptoms were extracted by two independent raters. The primary outcome measure was clinical remission at 24 h, 3 days and 7 days post-treatment. Analyses employed a random-effects model. RESULTS Data were synthesized from seven RCTs employing an intravenous infusion and one RCT employing intranasal ketamine, representing 73 subjects in parallel arms and 110 subjects in cross-over designs [n = 34 with bipolar disorder (BD), n = 149 with major depressive disorder (MDD)]. Ketamine was associated with higher rates of clinical remission relative to comparator (saline or midazolam) at 24 h [OR 7.06, number needed to treat (NNT) = 5], 3 days (OR 3.86, NNT = 6), and 7 days (OR 4.00, NNT = 6), as well as higher rates of clinical response at 24 h (OR 9.10, NNT = 3), 3 days (OR 6.77, NNT = 3), and 7 days (OR 4.87, NNT = 4). A standardized mean difference of 0.90 in favor of ketamine was observed at 24 h based on depression rating scale scores, with group comparisons revealing greater efficacy in unipolar depression compared to bipolar depression (1.07 v. 0.68). Ketamine was associated with transient psychotomimetic effects, but no persistent psychosis or affective switches. CONCLUSION Our meta-analysis suggests that single administrations ketamine are efficacious in the rapid treatment of unipolar and bipolar depression. Additional research is required to determine optimal dosing schedules, route, treatment schedules, and the potential efficacy of other glutamatergic agents.

Familial Aggregation of Suicide Explained by Cluster B Traits: A Three-Group Family Study of Suicide Controlling for Major Depressive Disorder

OBJECTIVE There is substantial evidence suggesting that suicide aggregates in families. However, the extent of overlap between the liability to suicide and psychiatric disorders, particularly major depressive disorder, remains an important issue. Similarly, factors that account for the familial transmission of suicidal behavior remain unclear. Thus, through direct and blind assessment of first-degree relatives, the authors conducted a family study of suicide by examining three proband groups: probands who committed suicide in the context of major depressive disorder, living depressed probands with no history of suicidal behavior, and psychiatrically normal community comparison probands. METHOD Participants were 718 first-degree relatives from 120 families: 296 relatives of 51 depressed probands who committed suicide, 185 relatives of 34 nonsuicidal depressed probands, and 237 relatives of 35 community comparison subjects. Psychopathology, suicidal behavior, and behavioral measures were assessed via interviews. RESULTS The relatives of probands who committed suicide had higher levels of suicidal behavior (10.8%) than the relatives of nonsuicidal depressed probands (6.5%) and community comparison probands (3.4%). Testing cluster B traits as intermediate phenotypes of suicide showed that the relatives of depressed probands who committed suicide had elevated levels of cluster B traits; familial predisposition to suicide was associated with increased levels of cluster B traits; cluster B traits demonstrated familial aggregation and were associated with suicide attempts among relatives; and cluster B traits mediated, at least in part, the relationship between familial predisposition and suicide attempts among relatives. Analyses were repeated for severity of attempts, where cluster B traits also met criteria for endophenotypes of suicide. CONCLUSIONS Familial transmission of suicide and major depression, while partially overlapping, are distinct. Cluster B traits and impulsive-aggressive behavior represent intermediate phenotypes of suicide.

Dysregulation of the sympathetic nervous system, hypothalamic-pituitary-adrenal axis and executive function in individuals at risk for suicide.

BACKGROUND Suicidal behaviour aggregates in families, and the hypothalamic-pituitary-adrenal (HPA) axis and noradrenergic dysregulation may play a role in suicide risk. It is unclear whether stress dysregulation is a heritable trait of suicide or how it might increase risk. We investigated stress reactivity of the autonomic nervous system and the HPA axis in suicide predisposition and characterized the effect of this dysregulation on neuropsychologic function. METHODS In this family-based study of first-degree relatives (n = 14) of suicide completers and matched controls with no family or personal history of suicidal behaviour (n = 14), participants underwent the Trier Social Stress Test (TSST). We used salivary α-amylase and cortisol levels to characterize stress reactivity and diurnal variation. We administered a series of neuropsychologic and executive function tests before and after the TSST. RESULTS Despite normal diurnal variation, relatives of suicide completers exhibited blunted cortisol and α-amylase TSST reactivity. Although there were no baseline differences in conceptual reasoning, sustained attention or executive function, the relatives of suicide completers did not improve on measures of inhibition upon repeated testing after TSST. Secondary analyses suggested that these effects were related to suicide vulnerability independent of major depression. LIMITATIONS The sample size was small, and the design prevents us from disentangling our findings from the possible traumatic consequences of losing a relative by suicide. CONCLUSIONS Blunted stress response may be a trait of suicide risk, and impairment of stress-induced executive function may contribute to suicide vulnerability.

The Effect of Genetic Variation of the Serotonin 1B Receptor Gene on Impulsive Aggressive Behavior and Suicide

Impulsive–aggressive behaviors (IABs) are regarded as possible suicide intermediate phenotypes, mediating the relationship between genes and suicide outcome. In this study, we aimed to investigate the putative relationship between genetic variation at the 5‐HT1B receptor gene, which in animal models is involved in impulse‐aggression control, IABs, and suicide risk. We investigated the relationship of variation at five 5‐HT1B loci and IAB measures in a sample of 696 subjects, including 338 individuals who died by suicide and 358 normal epidemiological controls. We found that variation at the 5‐HT1B promoter A‐161T locus had a significant effect on levels of IABs, as measured by the Buss–Durkee Hostility Inventory (BDHI). Suicides also differed from controls in distribution of variants at this locus. The A‐161T locus, which seems to impact 5‐HT1B transcription, could play a role in suicide predisposition by means of mediating impulsive–aggressive behaviors.

Repetitive transcranial magnetic stimulation (rTMS) for treating major depression and schizophrenia: a systematic review of recent meta-analyses

Abstract Background. In recent years, repetitive transcranial magnetic stimulation (rTMS) has been developed for the treatment of major depression (MD) and schizophrenia. Although rTMS has shown some promising findings, the lack of standardization in the methodology employed has resulted in discordant findings. Objectives. The objective of this systematic review was to summarize several meta-analytical studies exploring the efficacy of rTMS in either MD or schizophrenia in order to examine the methodologies that increase the efficacy of rTMS and to provide some recommendations for future studies. Methods. We searched the MEDLINE database for potentially relevant meta-analytic studies on the use of rTMS for treating major depression and schizophrenia published from January 2000 to October 2011. Results. Fifteen rTMS meta-analytical studies were reviewed (11 on MD and 5 on schizophrenia). Several variables were reviewed including outcome measures, side-effects of rTMS, site of stimulation, frequency and intensity of stimulation, and number of treatment sessions. Conclusions. Overall, rTMS appears to be an effective and promising therapeutic for both MD and schizophrenia.

What is specific to suicide in schizophrenia disorder? Demographic, clinical and behavioural dimensions

BACKGROUND Schizophrenia and schizoaffective disorder are diagnostic categories that are particularly at risk for suicide. A number of risk factors have been proposed to play a role in vulnerability to suicide, but it is unclear whether these are specific to certain diagnostic groups at risk for suicide or generalizable across disorders. It remains to be better understood what differentiates schizophrenic from non-schizophrenic suicides and whether or not these two groups share a common suicide liability. METHODS Five hundred and twenty seven consecutive suicides, 43 of whom met criteria for schizophrenia and schizoaffective disorder, were investigated by means of proxy-based interviews using structured diagnostic instruments and personality trait assessments. RESULTS Compared to other suicides, we found that schizophrenic and schizoaffective suicides presented comparably elevated levels of impulsive aggressive traits. They also had comparable levels of family history of suicidal behaviour among first degree relatives. Overall, schizophrenics and schizoaffective suicides met criteria for fewer psychiatric disorders, and were less likely to meet criteria for more than one disorder. Compared to suicides without schizophrenia or schizoaffective disorders, lower levels depressive disorders, of current and lifetime comorbid alcohol abuse, and personality disorders were found within those suicides who met criteria schizophrenia and schizoaffective disorders. CONCLUSIONS Elevated levels of impulsive-aggressive personality traits, considered as indicative of an elevated risk for suicide in other diagnostic categories, are also found among schizophrenic and schizoaffective suicide completers. Elevated levels of impulsive aggressive behaviours may serve as a common liability to suicide across major psychopathological categories, including schizophrenia and schizoaffective disorder.

Effectiveness and acceptability of deep brain stimulation (DBS) of the subgenual cingulate cortex for treatment-resistant depression: A systematic review and exploratory meta-analysis

BACKGROUND Deep brain stimulation (DBS) applied to the subgenual cingulate cortex (SCC) has been recently investigated as a potential treatment for severe and chronic treatment-resistant depression (TRD). Given its invasive and experimental nature, a comprehensive evaluation of its effectiveness and acceptability is of paramount importance. Therefore, we conducted the present systematic review and exploratory meta-analysis. METHODS We searched the literature for English language prospective clinical trials on DBS of the SCC for TRD from 1999 through December 2012 using MEDLINE, EMBASE, PsycINFO, CENTRAL and SCOPUS, and performed a random effects exploratory meta-analysis using Event Rates and Hedges׳ g effect sizes. RESULTS Data from 4 observational studies were included, totaling 66 subjects with severe and chronic TRD. Twelve-month response and remission rates following DBS treatment were 39.9% (95% CI=28.4% to 52.8%) and 26.3% (95% CI=13% to 45.9%), respectively. Also, depression scores at 12 months post-DBS were significantly reduced (i.e., pooled Hedges׳ g effect size=-1.89 [95% CI=-2.64 to -1.15, p<0.0001]). Also, there was a significant decrease in depression scores between 3 and 6 months (Hedges׳ g=-0.27, p=0.003), but no significant changes from months 6 to 12. Finally, dropout rates at 12 months were 10.8% (95% CI=4.3% to 24.4%). LIMITATIONS Small number of included studies (most of which were open label), and limited long-term effectiveness data. CONCLUSIONS DBS applied to the SCC seems to be associated with relatively large response and remission rates in the short- and medium- to long-term in patients with severe TRD. Also, its maximal antidepressant effects are mostly observed within the first 6 months after device implantation. Nevertheless, these findings are clearly preliminary and future controlled trials should include larger and more representative samples, and focus on the identification of optimal neuroanatomical sites and stimulation parameters.

Operationalizing cognitive vulnerability and stress from the perspective of the hopelessness theory: a multi-wave longitudinal study of children of affectively ill parents.

OBJECTIVES The current study tested the diathesis-stress component of the hopelessness theory (HT) in a sample of youth using (1) a weakest link approach towards operationalizing cognitive vulnerability (e.g. a childs degree of vulnerability is determined by his/her most depressogenic inferential style; DIS) and (2) an idiographic approach towards operationalizing high stress (e.g. high stress is when a child is experiencing a level of stress that is higher than his/her own average level of stress). We also examined whether the association between within-subject fluctuations in hassles and depressive symptoms in cognitively vulnerable youth was moderated by absolute stress levels (the between-subject effect of stress). DESIGN A multi-wave longitudinal design was used to examine whether the association between within-subject fluctuations in hassles and depressive symptoms was moderated by a depressogenic weakest link. METHODS At Time 1, 140 children (between 6 and 14 years of age) of parents with a history of major depressive episodes completed measures assessing DISs and depressive symptoms. Every 6 weeks, for the subsequent year, children completed measures assessing depressive symptoms and hassles. RESULTS The results of hierarchical linear modelling analyses indicated that a depressogenic weakest link was associated with greater elevations in depressive symptoms following elevations in hassles in girls but not in boys. CONCLUSIONS Results provide partial support for the applicability of the diathesis-stress component of the HT to youth. Integration of the current findings with those obtained in past research examining the diathesis-stress component of the hopelessness theory in youth suggests the utilization of an idiographic approach to examining vulnerability-stress theories may potentially lead to an increased understanding of gender differences in depression.

Sexual Orientation and Gender Identity in Youth Suicide Victims: An Exploratory Study

Objective: Our study was designed to explore additional outcome variables of a suicide case–control study to determine the association between sexual orientation and gender identity in suicide completion in children and adolescents. Method: Fifty-five child and adolescent suicide victims and 55 community control subjects were assessed using semi-structured, proxy-based interviews and questionnaires regarding sexual orientation and gender issues, psychopathological diagnoses, and service use. Results: In our sample, no significant differences between suicide victims and control subjects were found regarding same-sex sexual orientation nor intimidation related to same-sex sexual orientation. Suicide victims with same-sex sexual orientation were more likely than suicide victims without same-sex sexual orientation, to meet criteria for anxiety disorders. Within the month preceding their deaths, these youth were more likely to have consulted a health professional, a psychiatrist, as well as having been hospitalized, and were more likely to have consulted a psychiatrist in the last year. Conclusions: In our sample, same-sex sexual orientation and gender identity issues do not appear to be more prevalent among youth who die by suicide, compared with youth recruited from the general population, nor for same-sex sexual-related intimidation. While exhibiting comparable levels of general psychopathological diagnoses associated with suicide, suicide victims with same-sex sexual orientation were more likely to meet criteria for anxiety disorders and to have consulted mental health professionals before their deaths.

Specific Inhibition of Phosphodiesterase-4B Results in Anxiolysis and Facilitates Memory Acquisition

Cognitive dysfunction is a core feature of dementia and a prominent feature in psychiatric disease. As non-redundant regulators of intracellular cAMP gradients, phosphodiesterases (PDE) mediate fundamental aspects of brain function relevant to learning, memory, and higher cognitive functions. Phosphodiesterase-4B (PDE4B) is an important phosphodiesterase in the hippocampal formation, is a major Disrupted in Schizophrenia 1 (DISC1) binding partner and is itself a risk gene for psychiatric illness. To define the effects of specific inhibition of the PDE4B subtype, we generated mice with a catalytic domain mutant form of PDE4B (Y358C) that has decreased ability to hydrolyze cAMP. Structural modeling predictions of decreased function and impaired binding with DISC1 were confirmed in cell assays. Phenotypic characterization of the PDE4BY358C mice revealed facilitated phosphorylation of CREB, decreased binding to DISC1, and upregulation of DISC1 and β-Arrestin in hippocampus and amygdala. In behavioral assays, PDE4BY358C mice displayed decreased anxiety and increased exploration, as well as cognitive enhancement across several tests of learning and memory, consistent with synaptic changes including enhanced long-term potentiation and impaired depotentiation ex vivo. PDE4BY358C mice also demonstrated enhanced neurogenesis. Contextual fear memory, though intact at 24 h, was decreased at 7 days in PDE4BY358C mice, an effect replicated pharmacologically with a non-selective PDE4 inhibitor, implicating cAMP signaling by PDE4B in a very late phase of consolidation. No effect of the PDE4BY358C mutation was observed in the prepulse inhibition and forced swim tests. Our data establish specific inhibition of PDE4B as a promising therapeutic approach for disorders of cognition and anxiety, and a putative target for pathological fear memory.