David Baumeister

Childhood trauma and adulthood inflammation: A meta-analysis of peripheral C-reactive protein, Interleukin-6 and Tumour Necrosis Factor-α

Childhood trauma confers higher risk of adulthood physical and mental illness; however, the biological mechanism mediating this association remains largely unknown. Recent research has suggested dysregulation of the immune system as a possible biological mediator. The present paper conducted a meta-analysis to establish whether early-life adversity contributes to potentially pathogenic pro-inflammatory phenotypes in adult individuals. A systematic search of Pubmed, PsycINFO, EMBASE, Scopus and Medline identified 25 articles for the meta-analysis, including 18 studies encompassing a sample of 16 870 individuals for C-reactive protein (CRP), 15 studies including 3751 individuals for interleukin-6 (IL-6) and 10 studies including 881 individuals for tumour necrosis factor-α (TNF-α). Random-effects meta-analysis showed that individuals exposed to childhood trauma had significantly elevated baseline peripheral levels of CRP (Fisher’s z=0.10, 95% confidence interval (CI)=0.05–0.14), IL-6 (z=0.08, 95% CI=0.03–0.14) and TNF-α (z=0.23, 95% CI=0.14–0.32). Subgroup analyses for specific types of trauma (sexual, physical or emotional abuse) revealed that these impact differentially the single inflammatory markers. Moreover, meta-regression revealed greater effect sizes in clinical samples for the association between childhood trauma and CRP but not for IL-6 or TNF-α. Age, body mass index (BMI) and gender had no moderating effects. The analysis demonstrates that childhood trauma contributes to a pro-inflammatory state in adulthood, with specific inflammatory profiles depending on the specific type of trauma.

Inflammatory biomarker profiles of mental disorders and their relation to clinical, social and lifestyle factors

In the last few decades, mental health research has increasingly provided evidence supporting the role of inflammation in pathogenesis, course and treatment of mental disorders. With such a steep incline of research, resulting in a wealth of emerged findings, it has become difficult to follow developments within the field. The present review sets out to present the recent developments and to give an overview of the inflammatory profiles of depression, psychosis and bipolar disorder, as well as variations within these disorders. Moreover, mediating factors such as social environment and childhood experience are discussed, both in terms of their potential in elucidating the complex interface between the inflammation and other closely related biological systems, as well as the possibly confounding impact of various lifestyle factors. Whilst many issues in this fascinating area of research remain to be fully understood and elaborated, all current evidence suggests that inflammation plays a key role in mental disorders and may open up novel avenues for clinical treatment.

Effects of psychotropic drugs on inflammation: consequence or mediator of therapeutic effects in psychiatric treatment?

RationaleCurrent psychotropic medications have been shown to modulate immune activation. However, the effects of individual psychotropic agents on the immune system and how these might contribute to their efficacy remain largely unclear.ObjectiveThis paper aims to review previous literature on the effects of antidepressants and antipsychotics on the immune system, with a systematic review of in vitro findings, and discuss the relevance of these effects for the response to treatment and future drug development.ResultsInflammatory markers have been associated with fluctuations in clinical status and with treatment response both in depression and psychosis. The in vitro literature on antidepressants shows that some antidepressants, such as clomipramine and fluoxetine, more consistently decrease pro-inflammatory cytokines (interleukin (IL)-6, interferon (IFN)-γ, tumour necrosis factor (TNF)-α), whilst others (mirtazapine and venlafaxine) tend to increase their levels. However, any overall conclusion is challenged by several inconsistent findings, which appear partly dependent on different methodological approaches used. The in vitro studies on antipsychotics are even less clear-cut showing pro- and anti-inflammatory activity for the same antipsychotic agent (haloperidol, clozapine, risperidone) across different studies. We also noted inconsistencies between in vivo and in vitro literature, which could partly be attributed to the interaction in vivo with various biological systems or lifestyle factors that can modulate the immune system.ConclusionsInflammatory markers seem to hold potential for developing more individualised treatment strategies in the future. In this context, further research disentangling the differential immunomodulatory effects of different drugs could be used for tailoring treatment to specific individuals, according to their immune endophenotypes.

Classical hallucinogens as antidepressants? A review of pharmacodynamics and putative clinical roles

Hallucinogens have been part of spiritual practice for millennia, but controversy surrounding their mind-manifesting effects led to their proscription by the mid-20th century, largely without evidence of harm or toxicity and despite nascent data suggesting therapeutic utility in treating depressive illnesses. This review explores their pharmacodynamic actions and the current limited data on their clinic effectiveness. These drugs appear to exert their psychedelic effects through their agonist or partial agonist activity at the serotonergic 5-HT2A receptor, though they also have affinity for other metabotropic serotonin receptors. Hallucinogen binding affects a wide range of intracellular signalling pathways, the precise nature of which remains incompletely understood. They alter the serotonergic tone of brainstem raphe nuclei that project through the brain; they interact with receptors in the prefrontal cortex altering connectivity patterns and intracellular functioning; and they disrupt inhibitory control of sensory input via the thalamus to the cortex. The serotonergic system has long been implicated in anxiety and depressive disorders, and is a major target of most existing antidepressants. Classical hallucinogens alter the functioning of this system, but not in the same way current medications do: whilst there are identified receptors and neurotransmitter pathways through which hallucinogens could therein produce therapeutic effects, the neurobiology of this remains speculative at this time. There is currently an extremely limited but growing literature on hallucinogen safety and clinical application. The drugs appear well tolerated by healthy controls and clinical populations, and the rapid tolerance to repeated administration might reduce the possibility of dependency. Clinical trials reported over the past decade have generally shown positive therapeutic potential, but they are notably few in number. Legislative policy has had a freezing effect on evaluation of these compounds, a better understanding of which might improve our knowledge of the processes involved in consciousness, the neuropathology of depression, and potentially open up new pharmacological therapies.

The Interface of Stress and the HPA Axis in Behavioural Phenotypes of Mental Illness

Abnormalities of hypothalamic-pituitary-adrenal (HPA) axis function are one of the most consistent biological findings across several mental disorders, but many of the mechanisms underlying this abnormality as well as the potential contribution to behavioural phenotypes remain only partially understood. Interestingly, evidence suggests a U-curve, with dysregulation of the HPA axis towards both hyper- or hypoactivity manifesting as a risk to mental wellbeing. This review will elaborate on both the clinical and molecular role of the neuroendocrine stress system in depressive, psychotic and post-traumatic stress disorders and present some of the most recent findings that have shed light on the complex interface between environmental stressors, molecular mechanisms and clinical presentation. Crucially, plasticity of the HPA axis confers both vulnerability to adverse events, particularly so in early developmental stages, as well as hope for the treatment of mental disorder, as evidenced by changes in HPA functioning associated with remission of symptoms.

Legal highs: staying on top of the flood of novel psychoactive substances

There has been growing clinical, public, and media awareness and concern about the availability and potential harmfulness of so-called ‘legal highs’, which are more appropriately called new or novel psychoactive substances (NPS). A cat-and-mouse process has emerged wherein unknown chemists and laboratories are producing new, and as yet nonproscribed, compounds for human consumption; and as soon as they are banned, which they inevitably are, slightly modified analogues are produced to circumvent new laws. This rapidly changing environment, 81 new substances were identified in 2013 alone, has led to confusion for clinicians, psychopharmacologists, and the public at large. Our difficulties in keeping up with the process has had a two-fold negative effect: the danger of ignoring what is confusing; and the problem that some of the newer synthesized compounds appear ever more potent. This review aims to circumscribe a quick moving and growing field, and to categorize NPS into five major groups based upon their ‘parent’ compounds: stimulants similar to cocaine, amphetamines and ecstasy; cannabinoids; benzodiazepine based drugs; dissociatives similar to ketamine and phencyclidine (PCP); and those modelled after classic hallucinogens such as LSD and psilocybin. Pharmacodynamic actions, subjective and physical effects, harmfulness, risk of dependency and, where appropriate, putative clinical potentials are described for each class. Clinicians might encounter NPS in various ways: anecdotal reportage; acute intoxication; as part of a substance misuse profile; and as a precipitant or perpetuating factor for longer-term physical and psychological ill health. Current data are overall limited, and much of our knowledge and treatment strategies are based upon those of the ‘parent’ compound. There is a critical need for more research in this field, and for professionals to make themselves more aware of this growing issue and how it might affect those we see clinically and try to help: a brave new world of so-called ‘psychonauts’ consuming NPS will also need informed ‘psychotherapeutonauts’. The paper should serve as a primer for clinicians and interested readers, as well as provide a framework into which to place the new substances that will inevitably be synthesized in the future.

Taking the fuel out of the fire: Evidence for the use of anti-inflammatory agents in the treatment of bipolar disorders

BACKGROUND Inflammation has emerged as a potentially important factor - and thus putative pharmacological target - in the pathology of bipolar disorders. However to date no systematic evaluations of the efficacy of add on anti-inflammatory treatment for the depressive and manic episodes have been carried out. METHODS Sixteen articles were ultimately identified - by computer searches of databases (including PsycINFO, MEDLINE, and EMBASE), supplemented by hand searches and personal communication - as meeting study inclusion criteria. RESULTS Anti-manic effects were evaluated in two trials, one of adjunctive n-acetyl cysteine (NAC), one of omega-3 fatty acids (O3FA), and significant improvements only emerged for NAC. Celecoxib had a rapid but short-lived antidepressant effect. Despite limited effects of O3FA on symptoms, imaging data demonstrated alterations in neuronal functioning that might have longer-term therapeutic effects. Evidence was strongest for adjunctive NAC in bipolar depression though conclusions are limited by small sample sizes. LIMITATIONS Definitive conclusions are limited by the paucity of data, small study sizes, and the variability in methodology used. CONCLUSIONS Current evidence for aspirin or celecoxib is insufficient though further investigation of the potential of celecoxib in early illness onset is warranted. Variable evidence exists for add-on O3FA though an indication of short-term treatment effects on membrane fluidity and neuronal activity suggest longer follow-up assessment is needed. The strongest evidence emerged for NAC in depression and future studies must address the role of illness duration and patients׳ baseline medications on outcomes. Careful consideration of lithium toxicity in the elderly and renal impaired is essential.

Bupropion: a systematic review and meta-analysis of effectiveness as an antidepressant

Bupropion has been used as an antidepressant for over 20 years, though its licence for such use varies and it is typically a third- or fourth-line agent. It has a unique pharmacology, inhibiting the reuptake of noradrenaline and dopamine, potentially providing pharmacological augmentation to more common antidepressants such as selective serotonergic reuptake inhibitors (SSRIs). This systematic review and meta-analysis identified 51 studies, dividing into four categories: bupropion as a sole antidepressant, bupropion coprescribed with another antidepressant, bupropion in ‘other’ populations (e.g. bipolar depression, elderly populations) and primary evaluation of side effects. Methodologically more robust trials support the superiority of bupropion over placebo, and most head-to-head antidepressant trials showed an equivalent effectiveness, though some of these are hindered by a lack of a placebo arm. Most work on the coprescribing of bupropion with another antidepressant supports an additional effect, though many are open-label trials. Several large multi-medication trials, most notably STAR*D, also support a therapeutic role for bupropion; in general, it demonstrated similar effectiveness to other medications, though this literature highlights the generally low response rates in refractory cohorts. Effectiveness has been shown in ‘other’ populations, though there is an overall dearth of research. Bupropion is generally well tolerated, it has very low rates of sexual dysfunction, and is more likely to cause weight loss than gain. Our findings support the use of bupropion as a sole or coprescribed antidepressant, particularly if weight gain or sexual dysfunction are, or are likely to be, significant problems. However there are notable gaps in the literature, including less information on treatment naïve and first presentation depression, particularly when one considers the ever-reducing rates of response in more refractory illness. There are some data to support bupropion targeting specific symptoms, but insufficient information to reliably inform such prescribing, and it remains uncertain whether bupropion pharmacodynamically truly augments other drugs.

Novel psychoactive substances: types, mechanisms of action, and effects

#### What you need to know In 2016 the Psychoactive Substances Bill banned trading but not possession of all current and future novel psychoactive substances (NPS), sometimes incorrectly called “legal highs,” in an attempt to overcome rapid proliferation of these compounds. Over 560 substances are currently monitored by the European Monitoring Centre for Drugs and Drug Addiction, with 100 new agents identified in 2015 alone. Stimulants and synthetic cannabinoids account for the vast majority and are the types most commonly clinically encountered.1 Online purchases are increasing according to the 2016 Global Drug Survey,2 potentially in response to legislative changes, as is overall NPS use: lifetime consumption was reported by 8% of younger individuals in 2015, up from 5% in 2011, with figures relatively similar between sexes and different countries.3 Professionals report feeling less confident about managing NPS compared with established recreational drugs.4 There were 15 485 accesses to UK National Poisons Information Service TOXBASE relating to “legal highs,” “branded products,” synthetic cannabinoids, and mephedrone in 2014-15.5 Regarding harms from longer term dependence, the UK National Drug Treatment Monitoring System (NDTMS) report in 2015 described 3048 and 1370 adults with documented problematic use of mephedrone and “other” NPS respectively.6 Information on NPS primarily stems from case reports and …

Auditory verbal hallucinations and continuum models of psychosis: A systematic review of the healthy voice-hearer literature.

Recent decades have seen a surge of research interest in the phenomenon of healthy individuals who experience auditory verbal hallucinations, yet do not exhibit distress or need for care. The aims of the present systematic review are to provide a comprehensive overview of this research and examine how healthy voice-hearers may best be conceptualised in relation to the diagnostic versus ‘quasi-‘ and ‘fully-dimensional’ continuum models of psychosis. A systematic literature search was conducted, resulting in a total of 398 article titles and abstracts that were scrutinised for appropriateness to the present objective. Seventy articles were identified for full-text analysis, of which 36 met criteria for inclusion. Subjective perceptual experience of voices, such as loudness or location (i.e., inside/outside head), is similar in clinical and non-clinical groups, although clinical voice-hearers have more frequent voices, more negative voice content, and an older age of onset. Groups differ significantly in beliefs about voices, control over voices, voice-related distress, and affective difficulties. Cognitive biases, reduced global functioning, and psychiatric symptoms such as delusions, appear more prevalent in healthy voice-hearers than in healthy controls, yet less than in clinical samples. Transition to mental health difficulties is increased in HVHs, yet only occurs in a minority and is predicted by previous mood problems and voice distress. Whilst healthy voice-hearers show similar brain activity during hallucinatory experiences to clinical voice-hearers, other neuroimaging measures, such as mismatch negativity, have been inconclusive. Risk factors such as familial and childhood trauma appear similar between clinical and non-clinical voice-hearers. Overall the results of the present systematic review support a continuum view rather than a diagnostic model, but cannot distinguish between ‘quasi’ and ‘fully’ dimensional models. Healthy voice-hearers may be a key resource in informing transdiagnostic approaches to research of auditory hallucinations.