Neuroimaging Correlates of Treatment Response with Psychedelics in Major Depressive Disorder: A Systematic Review.

Preliminary evidence supports the use of psychedelics for major depressive disorder (MDD). However, less attention has been given to the neural mechanisms behind their effects. We conducted a systematic review examining the neuroimaging correlates of antidepressant response following psychedelic interventions for MDD. Through MEDLINE, Embase, and APA PsycINFO, 187 records were identified and 42 articles were screened. Six published studies and one conference abstract were included. Five ongoing trials were included from subjective outcomesTrials.gov. Our search covered several psychedelics, though included studies were specific to psilocybin, ayahuasca, and lysergic acid diethylamide. Three psilocybin studies noted amygdala activity and functional connectivity (FC) alterations that correlated with treatment response. Two psilocybin studies reported that FC changes in the medial and ventromedial prefrontal cortices correlated with treatment response. Two trials from a single study reported global decreases in brain network modularity which correlated with antidepressant response. One ayahuasca study reported increased activity in the limbic regions following treatment. Preliminary evidence suggests that the default mode and limbic networks may be a target for future research on the neural mechanisms of psychedelics. More data is required to corroborate these initial findings as the evidence summarized in this review is based on four datasets.

A qualitative systematic review of neurocognition in suicide ideators and attempters: Implications for cognitive-based psychotherapeutic interventions.

BACKGROUND: Growing evidence suggests cognitive deficits may represent neurocognitive markers with predictive utility in identifying those at risk for suicide. Characterizing these deficits may offer the opportunity to develop targeted interventions. AIM: The aim of this systematic qualitative review is to provide a synthesis of the published data on neurocognition in suicide ideators and attempters in order to clarify which neurocognitive targets may be most relevant to address using cognitive-based psychotherapeutic strategies in patients at risk for suicide. RESULTS: A total of 63 studies met criteria for inclusion. The most consistent findings were in depressed suicide attempters, where deficits in executive subdomains of inhibition, selective attention and decision-making, as well as in working memory, were identified. In contrast, no clear pattern of neurocognitive deficits emerged from studies in suicide ideators across diagnoses. CONCLUSIONS: More studies are needed to clarify the role of cognitive deficits in specific subtypes of individuals at risk for suicide. The findings are discussed in the context of promising research on cognitive remediation and other psychological interventions.

Age and haplotype variations within FADS1 interact and associate with alterations in fatty acid composition in human male cortical brain tissue.

UNLABELLED: Fatty acids (FA) play an integral role in brain function and alterations have been implicated in a variety of complex neurological disorders. Several recent genomic studies have highlighted genetic variability in the fatty acid desaturase (FADS1/2/3) gene cluster as an important contributor to FA alterations in serum lipids as well as measures of FA desaturase index estimated by ratios of relevant FAs. The contribution to alterations of FAs within the brain by local synthesis is still a matter of debate. Thus, the impact of genetic variants in FADS genes on gene expression and brain FA levels is an important avenue to investigate. METHODS: Analyses were performed on brain tissue from prefrontal cortex Brodmann area 47 (BA47) of 61 male subjects of French Canadian ancestry ranging in age from young adulthood to middle age (18-58 years old), with the exception of one teenager (15 years old). Haplotype tagging SNPs were selected using the publicly available HapMap genotyping dataset in conjunction with Haploview. DNA sequencing was performed by the Sanger method and gene expression was measured by quantitative real-time PCR. FAs in brain tissue were analysed by gas chromatography. Variants in the FADS1 gene region were sequenced and analyzed for their influence on both FADS gene expression and FAs in brain tissue. RESULTS: Our results suggest an association of the minor haplotype with alteration in estimated fatty acid desaturase activity. Analysis of the impact of DNA variants on expression and alternative transcripts of FADS1 and FADS2, however, showed no differences. Furthermore, there was a significant interaction between haplotype and age on certain brain FA levels. DISCUSSION: This study suggests that genetic variability in the FADS genes cluster, previously shown to be implicated in alterations in peripheral FA levels, may also affect FA composition in brain tissue, but not likely by local synthesis.

Altered expression of lipid metabolism and immune response genes in the frontal cortex of suicide completers.

BACKGROUND: Studies investigating the association between low cholesterol and suicidality have generated a range of ideas about how cholesterol might play a role in influencing suicide risk, extending studies to other aspects of lipid metabolism, as well as immune response, in relation to suicide. METHODS: We performed large-scale microarray gene expression analysis using the Affymetrix HG-U133 chipset and focused our investigation on the expression profile of genes related to lipid metabolism and immune response in post-mortem brains from suicide completers and comparison subjects. We used tissue from three regions of the frontal cortex (Brodmann areas (BA) 8/9, 11, and 47) from 22 male suicide completers, 15 of whom were diagnosed with major depressive disorder, and 13 male comparison subjects. RESULTS: Fatty acid desaturase (FADS1), leptin receptor (LEPR), phosphoinositide-3-kinase (class 2 alpha; PIK3C2A) and stearoyl-CoA desaturase (SCD) were consistently down-regulated in all three regions of the frontal cortex of depressed suicides compared to comparison subjects, and were among the genes for which significant correlations were observed between our microarray and real-time PCR data. LIMITATIONS: Given the absence of a non-suicidal depressed comparison group in this study, it cannot be ascertained whether the gene expression changes identified are associated with depression or suicide. CONCLUSIONS: Our findings suggest a role for lipid metabolism and immune response genes in depressed suicide completers and lend further support to the relationship between lipid metabolism and suicidality.

Fatty acid composition in postmortem brains of people who completed suicide.

OBJECTIVE: Cholesterol levels have been reported to be lower in suicidal patients, and alterations in blood levels of polyunsaturated fatty acids have been found in people with depression. Given that the evidence for the link between lipid metabolism and psychopathology thus far has almost exclusively hinged on alterations of these variables in blood, this study aimed to address whether similar alterations in fatty acids would be evident in the brains of people who complete suicide. METHODS: Using gas chromatography, we measured 49 different fatty acids in the orbitofrontal cortex and the ventral prefrontal cortex of people who had completed suicide with (n = 16) and without (n = 23) major depression and in control subjects (n = 19) with no current psychopathology and whose cause of death was sudden. RESULTS: Comparisons of fatty acids between the 3 groups did not reveal significant differences. CONCLUSION: Further research is required to better understand the link between fatty acids in the peripheral circulation and those in the central nervous system before determining whether fatty acids play a mediating role in suicidal behaviour.

Cholesterol content in brains of suicide completers.

An association between low levels of serum cholesterol and violent or suicidal behaviour has frequently been reported, but it remains unclear how cholesterol in the peripheral system might be related to the brain functions involved in mediating suicidal behaviour. To our knowledge, there have been no previous studies aimed at answering the important question of whether there are differences in cholesterol within the brains of suicide completers. In the present study, cholesterol content was measured in cortical and subcortical tissue of brains from 41 male suicide completers and 21 male controls that died of sudden causes with no direct influence on brain tissue. No significant differences in cholesterol content were found between suicides and controls in the frontal cortex, amygdala or hippocampus. However, when the suicide completers were stratified into violent (n=31) or non-violent (n=10) groups based on the method of death, violent suicides were found to have lower grey-matter cholesterol content overall compared to non-violent suicides [F(1,111)=4.75, p=0.03], specifically in the frontal cortex (t=-4.16, d.f.=37, p<0.0005). Further exploration of the frontal cortex revealed that violent suicides had lower cholesterol content compared to non-violent suicides in the orbitofrontal cortex (t=-2.01, d.f.=36, p=0.05) and the ventral prefrontal cortex (t=-2.49, d.f.=37, p=0.02). This study represents the first direct examination of cholesterol content in brain tissue from suicide completers, and the present findings provide added support for the relationship between low cholesterol and violent or suicidal behaviour.

Is violent method of suicide a behavioral marker of lifetime aggression?

OBJECTIVE: The main purpose of this study was to investigate whether the method of suicide is a valid behavioral marker of a lifetime history of aggression. METHOD: The authors applied the psychological autopsy method to investigate 310 individuals who committed suicide. They used structured clinical assessments and personality trait scales in interviews with family members of the deceased. RESULTS: Violent method was associated with a higher level of lifetime aggression and a higher level of impulsivity. In addition, violent method was associated with lifetime substance abuse or dependence and psychotic disorders. Controlling for age, sex, substance disorders, and other major psychopathology, the authors found that lifetime aggression and the interaction between impulsivity and aggressive behavior remained associated with violent method. CONCLUSIONS: These results support the use of violent method of suicide as a behavioral marker of a higher level of lifetime impulsive-aggressive behaviors.

Psychiatric risk factors for motor vehicle fatalities in young men.

BACKGROUND: Motor vehicle accident (MVA) fatalities are an important cause of death in young men. Psychiatric disorders have been shown to be risk factors for MVA, but only a few studies have investigated MVA fatalities. METHOD: A case-control study was carried out comparing 61 young male MVA fatalities in which the subject was the driver with an equal number of living male subjects matched for age (case by case with no more than 1 year's difference between case subjects and control subjects) with the accident group. We assessed both groups, using structured interviews and psychological autopsies. RESULTS: Our results suggest that cluster B personality disorders (borderline and [or] antisocial) (OR 3.54; 95%CI, 1.38 to 16.01) and substance use disorders in the last 6 months (OR 4.33; 95%CI, 1.42 to 9.25) increased the risk of dying in MVAs. In addition, we observed an age effect, where differences in cluster B personality disorders and substance use disorders in the last 6 months were only significantly more prevalent in case subjects aged 26 years or over, compared with control subjects of the same age. Drivers under age 25 years appeared to be comparable with control subjects on all measures of psychopathology. Finally, this interaction between cluster B personality disorders and age over 26 years was the only significant predictor of car fatalities (adjusted OR 16.25; 95%CI, 1.67 to 158.10). CONCLUSION: Borderline and antisocial personality disorders in which impulsive-aggressive behaviours play a central role and substance use disorders appear to be risk factors for young male deaths in MVAs. Interestingly, this effect seems to be specific to MVA case subjects aged 26 years or over.

Suicídio e ausência de psicopatologia em eixo I / Suicide and no axis I pathology

BACKGROUND: A razão por que aproximadamente 10 por cento das pessoas que cometem suicídio parecem ser psiquiatricamente normais ainda não está clara. Para melhor compreender este assunto, estudamos suicidas sem diagnóstico do eixo I e os comparamos com controles normais e com suicidas com psicopatologia do eixo I no que diz respeito a outras psicopatologias. MÉTODOS: 168 casos de suicídio foram examinados por meio de autópsia psicológica com o melhor informante disponível. Dezesseis casos não preencheram os critérios para um diagnóstico do eixo I; cada um desses casos foi pareado em idade e gênero com 52 casos de suicídio com transtorno do eixo I e com 110 controles normais. RESULTADOS: Dos 16 casos de suicídio, 14 pacientes sem diagnóstico do eixo I apresentaram anormalidades detectáveis à autópsia que eram mais semelhantes às encontradas nos pacientes suicidas com diagnóstico de eixo I do que no grupo vivo. Os dois grupos suicidas mostraram semelhanças no número total de tentativas prévias de suicídio, no número total de indivíduos com transtornos do eixo II e nos escores obtidos na medida dos comportamentos impulsivo-agressivos. CONCLUSÕES: Estes achados sugerem que a maioria dos indivíduos que cometeu suicídio e aparentou ser psiquiatricamente normal na autópsia psicológica possivelmente possuía algum processo psiquiátrico subjacente que o método da autópsia, da maneira como é comumente realizado, falhou em detectar.

Cholesterol metabolism and suicidality in Smith-Lemli-Opitz syndrome carriers.

OBJECTIVE: The authors examined the relationship between cholesterol metabolism and suicidality in carriers of Smith-Lemli-Opitz syndrome and their families. This population has a partial deficiency in 7-dehydrocholesterol reductase (DHCR7), the enzyme that catalyzes the last step in cholesterol biosynthesis. METHOD: Suicidal behavior, depression, misuse of alcohol and drugs, and family history of psychopathology, including attempted or completed suicide, were assessed by structured interview in 51 carriers of Smith-Lemli-Opitz syndrome and 54 matched comparison subjects. RESULTS: There were significantly more suicide attempters and completers among the biological relatives of Smith-Lemli-Opitz syndrome carriers than comparison subjects, but family history of psychopathology did not significantly differ between the groups. More suicide attempts were reported among Smith-Lemli-Opitz syndrome carriers than among the comparison subjects. CONCLUSIONS: These results, based on a unique study design, provide additional evidence supporting the relationship between cholesterol metabolism and suicidal behavior.

Suicide and no axis I psychopathology.

BACKGROUND: It is unclear why approximately 10% of suicide completers seem to be psychiatrically normal. To better understand this issue, we studied suicide completers without an axis I diagnosis and compared them, on measures of psychopathology other than axis I, to normal controls and suicide cases with axis I psychopathology. METHODS: 168 suicide cases were examined by way of a psychological autopsy with the best possible informant. Sixteen cases did not meet criteria for an axis I diagnosis; each of these cases was then age and gender matched to 52 suicide completers with an axis I disorder and 110 normal controls. RESULTS: Fourteen of sixteen suicide cases without an axis I diagnosis had detectable abnormalities that were more similar to the axis I diagnosed suicide group than to a living group. Both suicide groups were similar in the total number of past suicide attempts, the total number of individuals with an axis II disorder, and similar scores on measures of impulsive-aggressive behaviors. CONCLUSIONS: These findings suggest that most of the individuals who committed suicide and appeared psychiatrically normal after a psychological autopsy may probably have an underlying psychiatric process that the psychological autopsy method, as commonly carried out, failed to detect.

Alpha 2A adrenergic receptor gene and suicide.

Suicide is a complex trait resulting from the interaction of several predisposing factors, among which genes seem to play an important role. Alterations in the noradrenergic system have been observed in postmortem brain studies of suicide victims when compared to controls. The purpose of this study was to test the hypothesis that genetic variants of the alpha(2A) adrenergic receptor gene are implicated in suicide and/or have a modulatory effect on personality traits that are believed to mediate suicidal behavior. We studied a sample of suicides (N=110) and control subjects (N=130) for genetic variation at four loci, including three in the promoter region (g-1800t, c-1291 g and the g-261a) of the alpha(2A) adrenergic receptor gene, and a potentially functional locus, N251K, which leads to an amino acid change (asparagine to lysine). No significant differences were observed at the promoter loci in terms of allelic or genotypic distribution between suicides and controls. However, analysis of the functional polymorphism N251K revealed that the 251 K allele was only present among suicides, though only three suicide cases had this allele, two of which were homozygous. These results are preliminary. If confirmed, they suggest that variation at the alpha(2A) adrenergic receptor gene may play a role in a small proportion of suicide cases.

Investigation of completed suicide and genes involved in cholesterol metabolism.

BACKGROUND: Several lines of evidence support the association between low or lowered levels of serum total cholesterol and suicide. Genetic epidemiological studies suggest that genes predispose to suicide. Given that genes control many aspects of cholesterol biosynthesis and metabolism, one approach through which to explore the putative association between low cholesterol and suicide is through genetic studies. METHODS: We examined the potential role of five genes encoding proteins involved in cholesterol biosynthesis and transport in a total sample of 305 male Caucasian subjects, consisting of 145 suicide completers and 160 controls. We investigated variation in the HMG CoA reductase (HMGCR), 7-dehydrocholesterol reductase (DHCR7), lipoprotein lipase (LPL), low-density lipoprotein receptor (LDLR), and apolipoprotein E (APOE) genes. RESULTS: We were unable to detect significant differences in allele or genotype frequencies between the suicide cases and controls for any of the genes studied. No relationship was found between genotype and impulsivity or aggression as measured using the BIS and BDHI, respectively. LIMITATIONS: The limitations of this study are consistent with the typical limitations inherent in most genetic association studies involving complex behavioral traits. CONCLUSION: Although these genes are unlikely to play a major role in susceptibility to suicide, further studies in a larger sample are necessary to reveal the smaller genetic effects, if present.