is William P. Timmie Professor of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA

Understanding the immunological basis of disease has revolutionized the treatment of cancer and autoimmune and inflammatory disorders, benefitting millions of people with breakthrough immunotherapies. We now suspect that immunologic processes may also play a pivotal role in the development and maintenance of psychiatric disorders, opening an entire new avenue for novel strategies to prevent and treat psychiatric disease.

The immunologic processes connected to depression have received the most attention. A vast amount of data supports the hypothesis that the immune system in general and inflammation in particular, represent a pathway to pathology in a significant number of depressed patients. Although the relationship between inflammation and depression may at first glance appear straightforward, this relationship is much richer and more nuanced than is often believed. In hopes of embracing the complexity involved, 5 essential points that represent our current understanding of the field are presented.

Depression is not an inflammatory disorder

Probably the most important lessons that we have learned about inflammation and depression are that depression is not an inflammatory disorder and not every patient with depression has increased inflammation. Although a multitude of studies have demonstrated increased mean concentrations of a variety of inflammatory markers in depressed patients compared with controls-including reproducible increases in the inflammatory cytokines tumor necrosis factor (TNF), interleukin (IL)-1Î², IL-6 and the acute phase protein C-reactive protein (CRP)-there is considerable variability within the depressed population. Indeed, despite the question being asked repeatedly, we do not know the percentage patients in whom inflammation plays a role.

The difficulty in addressing this question is that the answer depends on the patient population being considered. The more inflammatory risk factors a patient has, the more likely he or she will have inflammation. There are a multitude of factors associated with increased inflammation (

) including treatment resistance. For example, 45% of patients enrolled in a study on treatment resistant depression had a CRP > 3 mg/L, which is considered high inflammation.

Another pivotal point is that increased inflammation not only occurs in depression but also in multiple other psychiatric diseases including bipolar disorder, anxiety disorders, personality disorders, and schizophrenia. These data suggest that inflammation is transdiagnostic in nature, occurring in subpopulations of patients within a number of psychiatric disorders.

Inflammation has specific effects on the brain and behavior

As we gain more insight into how inflammation affects the brain, it is becoming increasingly clear that there is a surprising specificity on the impact of inflammation on behavior. Such specificity is apparent in the neurocircuits and neurotransmitter systems that appear to be most affected by inflammation both in the context of the administration of inflammatory stimuli or in association with inflammatory markers in patients with depression or other psychiatric disorders (

). For example, administration of the inflammatory cytokine interferon (IFN)-Î± to patients or administration of typhoid vaccination or endotoxin to healthy volunteers has shown that inflammation affects subcortical and cortical brain circuits associated with motivation and motor activity as well as cortical brain regions associated with arousal, anxiety, and alarm.

Similar results have been found in patients with depression where increases in peripheral blood concentrations of the CRP were correlated with decreases in connectivity within motivation and reward circuits involving the ventral striatum and ventromedial prefrontal cortex (vmPFC), that in turn were associated with anhedonia.

 Greater inflammatory responses to stress as reflected by salivary concentrations of soluble TNF receptor 2 have also been correlated with activation of threat assessment circuits in the brain involving the dorsal anterior cingulate cortex (dACC) and insula.

 This latter effect of inflammation on threat and fear-related neurocircuitry may explain the emerging literature on the association of inflammatory markers with suicidal ideation and suicide attempts.

 Indeed, threat sensitivity has been shown to independently predict suicide risk, and data suggest that increased inflammatory markers may be preferentially associated with depressed patients who have attempted suicide.

In terms of the neurotransmitter systems involved, inflammation reduces the availability of monoamines by increasing the expression and function of the presynaptic reuptake pumps (transporters) for serotonin, dopamine, and norepinephrine and by reducing monoamine synthesis and release by decreasing enzymatic co-factors such as tetrahydrobiopterin.

 Cytokine-induced decreases in basal ganglia dopamine release have been observed in humans and directly correlated with reduced motivation in laboratory animals.

Inflammation also decreases relevant monoamine precursors by activating the enzyme indoleamine 

 dioxygenase, which breaks down tryptophan, the primary precursor for 5-HT, into kynurenine. Activated microglia can convert kynurenine into quinolinic acid, which can lead to excessive glutamate, an excitatory amino acid neurotransmitter. Excessive glutamate can lead to decreased brain-derived neurotrophic factor (BDNF) and excitotoxicity. Increased CRP has been directly correlated with increased glutamate in the basal ganglia of patients with depression.9 Finally, based on the inhibitory effects of inflammation on monoamine metabolism and BDNF, it is not surprising that inflammation is associated with a poor response to conventional antidepressants, whose efficacy relies in part on increasing monoamine availability and inducing BDNF and neurogenesis.

The immunology of inflammation in depression is only beginning to be understood

Our understanding of the immunology underlying inflammation in depression is limited to a small number of human studies in addition to animal studies. Thus, the relative contribution of innate and adaptive immune responses is unknown. One might suspect from the inflammatory mediators that are increased in the blood of depressed patients (eg, TNF, IL-1Î² and IL-6) that the primary drivers of inflammation in depression involve monocytes and activation of the innate immune response. Consistent with this notion is a recent report of increased perivascular monocytes/macrophages and monocyte chemoattractant protein (MCP)-1, a protein that attracts monocytes to the tissues in postmortem brain samples of presumably depressed suicide victims.

Findings from animal studies also suggest that stress-induced increases in catecholamines stimulate the release of monocytes from the bone marrow.2 Once in the blood, these monocytes encounter danger- or microbial-associated molecular patterns derived from stress-induced alterations in metabolism or microbial products from the gut that in turn activate inflammatory signaling pathways such as nuclear factor ÎºB (BF-ÎºB) leading to TNF and IL-6 as well as the imflammasome, which leads to the production of IL-1. TNF in turn has been shown to activate microglia to produce MCP-1, attracting monocytes to the brain notably in areas that regulate fear and anxiety including the amygdala.11 Recent data indicate that chronic social stress in laboratory animals can also lead to permeability in the blood – brain barrier that allows peripheral inflammatory signals including IL-6 to enter the brain in regions relevant to motivation and reward.

 Consistent with these laboratory animal data, peripheral blood immune cells from depressed patients have shown evidence of activation of both nuclear factor ÎºB and the inflammasome.

Despite evidence that monocytes and the innate immune response play a pivotal role in effects of inflammation on the brain, there is growing evidence to suggest that T cells and the adaptive immune response may also be involved.14 Decreased anti-inflammatory T regulatory cells and increased hyperinflammatory Th17 cells have been described in depressed patients and animal models of depression.

 Moreover, T cells and their production of IL-4 have been associated with resilience to stress and depression in laboratory animal models.

 These data are especially intriguing given recent characterization of the lymphatic system within CNS that allows the T cells to patrol the brain.

 Whether inflammatory responses are primarily driven by innate immune responses and monocytes versus the adaptive immune response and T cells will have profound implications for immunotherapeutic targeting of the immune system to treat depression.

Inflammation is related to treatment response

A major advantage of a pathophysiologic process that is believed to largely emanate from the periphery and spread to the brain is the opportunity to use blood tests to identify specific individuals for treatment targeting and ultimately precision care. Indeed, inflammatory markers alone or in combination have been shown to predict treatment response to conventional antidepressants and psychotherapy as well as advanced treatment strategies such as ketamine and anti-cytokine immunotherapy.

 Unfortunately, these studies are post hoc in nature, and no study has yet to prospectively assign patients with one or more level of inflammatory marker to a given treatment and predict response.

The greatest challenge is to determine which inflammatory marker(s) exhibits the greatest predictive value, while also being readily available for clinical application. Findings suggest that individuals with a CRP >1mg/L, which is the cut off for moderate inflammation, were less likely to respond to SSRIs.

 High CRP was also shown to predict response to the anti-inflammatory drug infliximab, an inhibitor of TNF.

 Given the relative availability of CRP in clinics and hospitals throughout the US and elsewhere, it may be that until other data are available, clinicians can use CRP as a general yardstick for inflammatory load.

There has been recent interest in identifying inflammation directly in the brain of depressed patients using positron emission tomography to identify activated microglia reflected by upregulation of the translocator protein (TSPO).

 Although there has been an assumption that increased TSPO binding signals neuroinflammation, the TSPO ligand is not able to distinguish microglia that are activated to perform important neuroprotective and neuroregulatory functions from microglia that are inflammatory. Therefore, these ligands are not ready for prime time, and results from the published literature using TSPO ligands should be interpreted with caution.

Clearly, there is much to be learned about the relationship between depression and inflammation. Nevertheless, the most exciting aspects of this work are the clear therapeutic implications ranging from blocking inflammation to targeting the downstream effects of inflammation on neurotransmitter systems and neurocircuits to implementing lifestyle interventions that reduce inflammation (

Several clinical trials are underway using immunotherapies that target TNF and IL-6. In each instance, a precision medicine approach is being taken: individuals with increased inflammation of CRP >3 mg/L are being treated. Whether targeting these cytokines versus targeting T cell-derived cytokines such as IL-17 is more efficacious and for whom remains to be determined. In addition, studies have suggested that both minocycline, which blocks microglial activation, and inhibitors of the inflammatory mediator cyclooxygenase (COX)-2 have antidepressant efficacy.18 However, more data are needed, given that precision targeting of patient populations with high inflammation has not been incorporated into the clinical trial design of these studies. Based on the impact of inflammation on dopaminergic and glutamatergic pathways, drugs that enhance dopamine signaling or block glutamate receptors may be especially relevant for patients with depressive symptoms and increased inflammation.

Dr Miller reports no conflicts of interest concerning the subject matter of this article.

 Raison CL, Rutherford RE, Woolwine BJ, et al. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry. 2013;70:31-41.

 Capuron L, Pagnoni G, Drake DF, et al. Dopaminergic mechanisms of reduced basal ganglia responses to hedonic reward during interferon alfa administration. Arch Gen Psychiatry. 2012;69:1044-1053.

 Eisenberger NI, Berkman ET, Inagaki TK, et al. Inflammation-induced anhedonia: endotoxin reduces ventral striatum responses to reward. Biol Psychiatry. 2010;68:748-754.

 Harrison NA, Voon V, Cercignani M, et al. A neurocomputational account of how inflammation enhances sensitivity to punishments versus rewards. Biol Psychiatry. 2016;80:73-81.

 Felger JC, Li Z, Haroon E, et al. Inflammation is associated with decreased functional connectivity within corticostriatal reward circuitry in depression. Mol Psychiatry. 2016;21:1358-1365.

 Slavich GM, Way BM, Eisenberger NI, et al. Neural sensitivity to social rejection is associated with inflammatory responses to social stress. Proc Natl Acad Sci USA. 2010;107:14817-14822.

 Brundin L, Bryleva EY, Thirtamara Rajamani K. Role of inflammation in suicide: from mechanisms to treatment. Neuropsychopharmacol. 2017;42:271-283.

 Venables NC, Sellbom M, Sourander A, et al. Separate and interactive contributions of weak inhibitory control and threat sensitivity to prediction of suicide risk. Psychiatry Res. 2015;226:461-466.

 Haroon E, Fleischer CC, Felger JC, et al. Conceptual convergence: increased inflammation is associated with increased basal ganglia glutamate in patients with major depression. Mol Psychiatry. 2016;21:1351-1357.

 Torres-Platas SG, Cruceanu C, Chen GG, et al. Evidence for increased microglial priming and macrophage recruitment in the dorsal anterior cingulate white matter of depressed suicides. Brain Behav Immun. 2014;42:50-59.

 McKim DB, Weber MD, Niraula A, et al. Microglial recruitment of IL-1beta-producing monocytes to brain endothelium causes stress-induced anxiety. Mol Psychiatry. April 4, 2017; Epub ahead of print.

 Menard C, Pfau ML, Hodes GE, et al. Social stress induces neurovascular pathology promoting depression. Nat Neurosci. 2017;20:1752-1760.

 Miller AH, Raison CL. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol. 2016;16:22-34.

 Miller AH. Depression and immunity: a role for T cells? Brain Behav Immun. 2010;24:1-8.

 Beurel E, Harrington LE, Jope RS. Inflammatory T helper 17 cells promote depression-like behavior in mice. Biol Psychiatry. 2013;73:622-630.

 Brachman RA, Lehmann ML, Maric D, et al. Lymphocytes from chronically stressed mice confer antidepressant-like effects to naive mice. J Neurosci. 2015;35:1530-1538.

 Louveau A, Smirnov I, Keyes TJ, et al. Structural and functional features of central nervous system lymphatic vessels. Nature. 2015;523:337-341.

 Miller AH, Haroon E, Felger JC. Therapeutic implications of brain-immune interactions: treatment in translation. Neuropsychopharmacol. 2017;42:334-359.

 Uher R, Tansey KE, Dew T, et al. An inflammatory biomarker as a differential predictor of outcome of depression treatment with escitalopram and nortriptyline. Am J Psychiatry. 2014;171:1278-1286.

 Jha MK, Minhajuddin A, Gadad BS, et al. Can C-reactive protein inform antidepressant medication selection in depressed outpatients? Findings from the CO-MED trial. Psychoneuroendocrinol. 2017;78:105-113.

 Setiawan E, Wilson AA, Mizrahi R, et al. Role of translocator protein density, a marker of neuroinflammation, in the brain during major depressive episodes. JAMA Psychiatry. 2015;72:268-275.

Articles

Immunologic processes may play a pivotal role in the development and maintenance of psychiatric disorders, opening an entire new avenue for novel strategies to prevent and treat psychiatric disease.

Five Things to Know About Inflammation and Depression

is Associate Professor, Icahn School of Medicine, Mount Sinai, New York, NY, and Director, Trauma and Recovery Services Clinic, James J. Peters Veterans Affairs Medical Center, Bronx.

is Professor of Psychiatry, Icahn School of Medicine, Mount Sinai, and Director, Mental Health Care Center, James J. Peters Veterans Affairs Medical Center.

In addition to psychosocial problems, there is a growing realization that PTSD may also lead to or exacerbate chronic medical health conditions. Several large cohort 

 demonstrate a prospective association between PTSD symptoms and cardio-metabolic disorders, such as myocardial infarction, stroke, type 2 diabetes mellitus, and coronary heart disease.

 The associations generally persist after adjusting for comorbid depression, which occurs in about half of all PTSD cases and findings are consistent across civilian and veteran samples.

The association between PTSD and medical illness appears to differ by race and ethnicity: black and Latino adults with PTSD are at greater risk relative to whites. The impact of sex and gender on this association also warrants further examination as many of the large prospective studies have been conducted using same-sex cohorts.

More recently, PTSD has been linked with autoimmune disorders and neurodegenerative diseases. 

 reported that patients with PTSD had a greater risk for thyroiditis, inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, and lupus erythematosus. Findings from this retrospective cohort of more than 600,000 Iraq and Afghanistan veterans were not associated with age, race, or gender.

The temporal association between PTSD and autoimmune disorders has not been studied extensively. However, results from one longitudinal cohort 

 of women showed that the onset of trauma exposure and PTSD symptoms preceded the development of lupus erythematosus.

 The public health significance of understanding why and how trauma exposure/PTSD are linked to medical illness is enormous. Recent results from gene expression studies offer some intriguing research possibilities for investigation.

Is PTSD symptom severity associated with metabolic and inflammatory markers?

Genome-wide transcription studies of trauma exposure and PTSD have identified specific genes, as well as causal pathways that implicate dysregulation of the immune system. 

 undertook a mega-analysis using the results from 5 PTSD transcriptome studies. They observed that PTSD was associated with differential expression in genes that regulate innate immunity, cytokine production, and type I interferon signaling. The study included more than 225 cases and 300 controls, which allowed for sub-analyses by gender and trauma type.

Lower expression of cytokine-related genes was observed in men exposed to interpersonal trauma relative to women exposed to interpersonal trauma or men exposed to combat. Further work is needed to explore whether gene expression differences associated with gender and trauma-type, which may carry over to observed group differences in the expression of chronic medical illness.

These genome-wide studies complement an established body of research on PTSD biomarkers that have focused extensively on the stress response, including 

 of the hypothalamic-pituitary-adrenal (HPA) axis.

 Stress exposure initiates downstream release of endogenous glucocorticoids (GCs), which bind to GC receptors on target metabolic and immune system tissue (eg, adipose tissue, skeletal muscle, pancreas). Following stress exposure, increases in GC activity lead to immunosuppression, increases in metabolic activity, and negative feedback of the HPA axis to establish homeostasis. The link between PTSD and chronic illness may stem from the effects of long-term disruption in GC functioning-as observed in PTSD-which contribute to sustained low-grade inflammation that damages target organs.

Findings have not always been consistent in studies of cross-sectional associations between PTSD symptoms and inflammatory markers. A recent 

 demonstrated that PTSD is associated with higher interleukin 6 (IL-6), interleukin (IL)-1Î², tumor necrosis factor (TNF) Î±, and interferon (IFN)-Î³ relative to controls.

 Also relevant is the prospective association between elevated C-reactive protein, an inflammatory marker of cardiovascular disease risk and the development of PTSD in 

 Similarly, higher IL-6 levels measured within 24 hours of a motor vehicle accident 

 PTSD symptoms in children and adolescents.

While some inflammatory activity may relate to psychotropic medication use, comorbid depression, or even trauma exposure itself, there is little doubt that PTSD is associated with immune system functioning. For example, see 

 who report no group differences in some of these measures in combat-exposed veterans with and without PTSD; this suggests that trauma exposure by itself may lead to increased inflammatory activity.

Does behavior mediate the relationship between PTSD and chronic health problems?

It is important to understand whether the inflammatory signature associated with PTSD reflects an extension of trauma-related pathophysiology, or whether it is an inevitable outcome of the behaviors that are associated with PTSD (eg, tobacco use, physical inactivity, imprudent dietary choices, disrupted sleep). If the inflammatory signal is an extension of trauma-related consequences that associate with, or possibly even lead to, other medical illnesses, this would suggest that PTSD is part of a larger systemic illness linked to psychological trauma.

Evidence-based psychotherapies for PTSD address psychological symptoms, but it is not known whether they also affect the immune system. However, the presence of markers of inflammation and metabolic dysfunction (eg, elevated lipid profile, weight gain or increase in waist circumference, insulin resistance) in people with PTSD suggests a need for a more comprehensive approach to the biomedical consequences of trauma.

Does pharmacotherapy for PTSD affect inflammatory markers?

If PTSD is causally associated with disruption of the immune system, interventions that directly target inflammatory markers might result in improved psychological and biomedical outcomes. Many people with PTSD are treated with psychotropic medications, but to date, there have been only a few attempts to develop novel pharmacotherapeutic agents for PTSD. FDA-approved SSRIs are associated with reduced inflammation and may have both 

One study examined changes in inflammatory markers following treatment of PTSD with paroxetine.

 Findings from this open trial do not show a decline in Il-6 despite a decline in PTSD symptoms. In contrast, SSRI treatment of depression is associated with a decline in cytokines. Sertraline and transcranial direct current treatment of depression were associated with declines in 6 of 7 cytokines in a randomized clinical trial.

Some of the novel PTSD pharmacotherapy approaches currently under investigation may also have the added benefit of targeting the immune system. One of the exciting developments in pharmacotherapy involves the use of glucocorticoid-related drugs to either prevent the development of PTSD, augment the gains of psychotherapy, or treat symptoms of chronic PTSD.

 Glucocorticoids are primarily used in a variety of medical ailments because of their anti-inflammatory properties.

Ketamine, an NMDA-receptor antagonist, is under investigation for PTSD. Findings indicate that it influences cytokine production in animal models.

 Although controversial in some settings as a treatment option, cannabinoids have immunosuppressive properties.

 The anti-inflammatory properties of these agents may augment the potentially beneficial effects on psychological symptoms.

An intriguing possibility is whether these and other medications for PTSD exert direct benefits on symptoms as a result of their influence on the immune system. If so, it is critical to consider the broader implications of the inflammatory signature of PTSD and its psychiatric and medical comorbidities.

The link between PTSD and chronic illness has been established but the potential role of immune system markers in mediating this association is only beginning to be examined. As new psychotherapeutic and pharmacological treatments are developed, there is an opportunity to examine the relationships between inflammatory markers and symptoms as they change over time.

Future research should examine how and whether psychotherapy affects inflammatory markers, and also to determine the extent to which inflammation is reduced by medications that alleviate PTSD symptoms. It is possible that the growing interest in alternative therapies for PTSD such as meditation, yoga, acupuncture, and other interventions that increase physical activity or alter dietary intake may provide benefits through their anti-inflammatory effects.

It is also important to examine whether the association between PTSD and immune markers is part of a broader association between mental illness and poor health or whether there is specificity between trauma exposure and particular markers and disease outcomes. Moreover, it is important to identify the contributions of trauma type, sex, race, and ethnicity to these associations.

The authors report no conflicts of interest concerning the subject matter of this article.

 Koenen KC, Sumner JA, Gilsanz P, et al. 

Post-traumatic stress disorder and cardiometabolic disease: improving causal inference to inform practice

 O’Donovan A, Cohen BE, Seal KH, et al. 

Elevated risk for autoimmune disorders in iraq and afghanistan veterans with posttraumatic stress disorder

 Roberts AL, Malspeis S, Kubzansky LD, et al. 

Association of trauma and posttraumatic stress disorder with incident systemic lupus erythematosus in a longitudinal cohort of women

 Breen MS, Tylee DS, Maihofer AX, et al. 

PTSD blood transcriptome mega-analysis: shared inflammatory pathways across biological sex and modes of trauma

 Yehuda R, Hoge CW, McFarlane AC, et al. 

 Passos IC, Vasconcelos-Moreno MP, Costa LG, et al. 

Inflammatory markers in post-traumatic stress disorder: a systematic review, meta-analysis, and meta-regression

 Eraly SA, Nievergelt CM, Maihofer AX, et al. 

Assessment of plasma C-reactive protein as a biomarker of posttraumatic stress disorder risk

 Pervanidou P, Kolaitis G, Charitaki S, et al. 

Elevated morning serum interleukin (IL)-6 or evening salivary cortisol concentrations predict posttraumatic stress disorder in children and adolescents six months after a motor vehicle accident

 Lindqvist D, Wolkowitz OM, Mellon S, et al. 

Proinflammatory milieu in combat-related PTSD is independent of depression and early life stress

 Galecki P, Mossakowska-WÃ³jcik J, Talarowska M. 

The anti-inflammatory mechanism of antidepressants: SSRIs, SNRIs

Prog Neuropsychopharmacol Biol Psychiatry

 Bonne O, Gill JM, Luckenbaugh DA, et al. Corticotropin-releasing factor, interleukin-6, brain-derived neurotrophic factor, insulin-like growth factor-1, and substance P in the cerebrospinal fluid of civilians with posttraumatic stress disorder before and after treatment with paroxetine. 

 Brunoni AR, Machado-Vieira R, Zarate CA, et al. Cytokines plasma levels during antidepressant treatment with sertraline and transcranial direct current stimulation (tDCS): results from a factorial, randomized, controlled trial. 

 Yehuda R, Golier J. Is there a rationale for cortisol-based treatments for PTSD? 

 Tan S, Wang Y, Chen K, et al. Ketamine alleviates depressive-like behaviors via down-regulating inflammatory cytokines induced by chronic restraint stress in mice.

 Katchan V, David P, Shoenfeld Y. Cannabinoids and autoimmune diseases: a systematic review. 

2016 Jun;15(6):513-28. doi: 10.1016/j.autrev.2016.02.008. Epub 2016 Feb 11.

In addition to psychosocial problems, there is a growing realization that PTSD may also lead to or exacerbate chronic medical health conditions.

Is PTSD a Systemic Disorder?

In 1897, the French sociologist Ãmile Durkheim (1858-1917) published 

Le suicide: Ãtude de sociologie [Suicide: A Study in Sociology]

. With it, Durkheim largely succeeded in achieving one of his main goals-to use an empirical analysis of the subject of suicide to launch the field of modern scientific sociology. Reading the book today, one is still impressed by its innovative methods. For example, its epidemiological approach based on international statistical data and its often surprising findings-for one, that suicide rates rose not during social crises, but rather at times when governing norms were breaking down.

While the work has been hailed as a founding text for the social sciences, historians have shown that Durkheim was perhaps less a pioneer than beneficiary of generations of research. As historian Daryl Lee puts it, the book “marks not the beginning but the culmination of nearly a century of intense anxiety and debate over the subject of suicide.”

 What for centuries had been considered a matter for clergy, theologians, and philosophers alone to comment on became in the 19th century a problem that increasingly drew the attention of psychiatrists and sociologists. Why did things change?

If we look back to ancient Greece and Rome, philosophers there considered it a matter of debate whether it was morally acceptable to end one’s life. Intellectuals such as Socrates and Cato, both suicide completers, continued to enjoy respectable reputations after their passing. Christian Europe, however, expressed a far less tolerant attitude toward self-inflicted death. For over a thousand years, Christian thinkers shared the aversion to suicide of St. Augustine (354–430), who held the act to be an arrogant refusal to submit to God's will; it was widely accepted, He and He alone rightfully decided on when an individual’s life should come to an end. As such, suicide was deemed a crime and the bodies of suicide completers were often desecrated and their possessions confiscated.

A shift in thinking began to take place between 1500 and 1800. While intellectuals of the 16th and early-17th centuries continued to pronounce suicide to be a moral abomination, some Enlightenment figures of the 18th century like Voltaire (1694–1778) and David Hume (1711–1776) argued for its legitimacy under certain situations. Historians examining judicial and church records have shown that in between these 2 periods, local authorities throughout Europe were slowly decriminalizing suicide, believing the penalties imposed on the corpses and estates of victims an unjustified burden on family members. Popular attitudes at the time also appear to have been evolving, as people gradually attributed suicides not to moral failings or the devil, but to deep emotions such as grief.

 This opened the way in the 1700s for reform-minded thinkers to begin pathologizing suicide as an expression of melancholy.

Clinical observers and researchers began taking up the subject in the early 19th century. In 1807, Danish physician Heinrich Callisen (1740–1824) dubbed it a form of illness and others soon followed suit.

 This was not due to the emergence of any new clinical evidence, however. Rather, legal and judicial changes in defining criminal responsibility inspired debate within psychiatry over a range of issues: the possibility of “partial” insanities, the existence of emotional and volitional forms of madness, as well as whether suicide should be treated simply as a symptom of an altered state of mind. On the latter question, some-like the famed French psychiatrist Jean-Ãtienne Esquirol (1772–1840)-generally believed it to be “a disorder of the emotions,” a view a later writer in 1857 would criticize as “. . . a dangerous and serious mistake which can give rise to undesirable moral consequences.”

At the time, the debate within psychiatry represented only one thread of the discussion over suicide. In the early 19th century, there was widespread perception that the incidence of suicide was rising. Whether this was so is difficult to judge. What we do know, however, is that this was exactly the moment when governments began to concertedly collect statistics on suicide as part of a broad effort aimed at developing a more empirically-informed public policy.

While interest in the regularities of birth, marriage, and death rates dated back to the 18th century, during the 1830s the field of what was called “moral statistics” was ever more drawn to deviant acts like crime, alcoholism, and suicide. For moral statisticians, like the Belgian Adolphe Quetelet (1796–1874), the fact that these morally corrupt and seeming irrational actions followed consistent patterns in their incidence, prevalence, and distribution demonstrated that human behavior-like the rest of the natural world-followed certain laws. And these laws, he thought, could be scientifically discovered and analyzed. Here was compelling proof of the need for a social science on par with the physical sciences.

 Thus, 2 lines of research emeged in 2 emerging fields, one rooted in psychiatry, the other in sociology. The 2 paths certainly diverged from one another: psychiatrists remained most interested in the psychopathology and treatment of individuals. Social scientists were drawn to identifying and influencing collective patterns.

Nevertheless, there were points where the interests of the 2 groups overlapped. Both statistician AndrÃ©-Michel Guerry (1802–1866) and physician Brierre de Boismont (1797–1881), for instance, separately took it upon themselves to classify and analyze the motivations of those committing suicide. Pouring over the letters, notes, and writings of thousands of victims, they sought out trends that might be common among those attempting to kill themselves.

But what continued to worry many analysts in both camps, however, was what seemed to be the shockingly high suicide rate in contemporary society. Thomas Masaryk in his 1881 study of the topic put it bluntly: suicide was “the sickness of our time.” It appeared to be not just an epidemic in, but also endemic to the modern world. What was one to make of this?

The growing influence of Darwinian evolutionary theory moved some to search for answers there. The physician and writer Max Nordau (1849–1923) argued that the rising suicide rate reflected a more general pattern of “degeneration,” an evolutionary regression of the human race caused by society’s neglect of the moral and hygienic health of civilized peoples.

Others, however, wondered whether the evolutionary connections between humans and other animals meant that suicide could be found in other species. Scottish alienist William Lauder Lindsay (1829–1880) believed so. A critic of the use of mechanical restraints and an advocate for psychotherapy in asylums, Lindsay argued that evidence showed that animals did commit suicide just like humans, not as “the simple product of malady, but of malady aggravated by mismanagement.” In other words, it was due to neglect and abuse. The famous British psychiatrist Henry Maudsley (1835–1918) begged to differ. He categorically dismissed the notion of animal suicide. Non-humans, he contended, lacked the capacity to deliberately seek their own deaths, and he criticized Lindsay for sacrificing scientific assessment in the service of a “spirit of romance.”

Others saw less value in evolutionary arguments, opting instead to focus on recent historical changes. Durkheim entered the debate, emphasizing the impact modern secular and consumer values had on unmooring individuals from their familiar moral anchors. He was hardly the first to argue along these lines. Almost 2 decades earlier, the Italian physician Enrico Morselli (1852–1929) published Suicide: An Essay on Comparative Moral Statistics (1879), in which he related contemporary suicides to the rise in the unsatisfied desires and unregulated self-gratification characteristic of modern life.

By century's end, many researchers concluded that suicide represented not so much an illness as a symptom–a response by some to the challenges posted by living in the modern world.

is Associate Professor of Modern History and Former Director of the Science, Technology, and Society Program at Penn State University; he is also Section Editor for Psychiatric Times' History of Psychiatry

 Lee D. Accounting for self-destruction: Morselli, moral statistics, and the modernity of suicide. Intellect Hist Rev. 2009;19:337.

 Watt JR. Introduction: toward a history of suicide in early modern Europe. From Sin to Insanity: Suicide in Early Modern Europe. Ithaca: Cornell University Press; 2004: 1-8.

 BÃ¤hr A. Between self-murder and suicide: the modern etymology of self-killing. J Soc Hist. 2013;46:620-632.

 Goldney RD, Schioldann JA, Dunn KI. Suicide research before Durkheim. Health Hist. 2008;10:73-89.

 Berrios GE, Mohanna M. Durkheim and French psychiatric views on suicide during the 19th century: a conceptual history. Br J Psychiatry. 1990;156:1-9.

 Porter TM. The Rise of Statistical Thinking, 1820-1900. Princeton: Princeton University Press; 1986.

 Pick D. Faces of Degeneration: A European Disorder, c 1848-1918. Cambridge: Cambridge University Press; 1989.

 Ramsden E, Wilson D. The suicidal animal: science and the nature of self-destruction. Past Present. 2014;224:201-242.

In 1897, the French sociologist Émile Durkheim (1858-1917) published Le suicide: Étude de sociologie [Suicide: A Study in Sociology]. With it, Durkheim largely succeeded in achieving one of his main goals.

A “Sickness of Our Time”: How Suicide First Became a Research Question

Providing psychiatric care for college students is different from treating other grown-ups. These emerging adults are in the midst of a tremendous emotional growth spurt and a leap of neurocognitive maturation. During this bewildering life transition, they often cannot articulate straightforwardly what bothers them. They appear mercurial: at times, they may speak in hyperbole and sound very dramatic. At other times, they shroud what ails them in secrecy because of embarrassment, fear, and hopelessness. Eventually, school stress and academic performance problems propel students to seek assistance. Mental health clinicians attending to this population need to keep an open mind and consider a host of differential diagnoses.

"Jerry" is a 19-year-old sophomore at a liberal arts college in the Northeast who wants to transfer to a prestigious business school. Two months into the fall semester and 1 week before midterms, Jerry reluctantly comes to the counseling service of his college. His dean accompanies him after receiving several alerts from professors about flagging academic performance.

Jerry unenthusiastically agrees to meet with a psychiatrist. He appears tired and says that he feels unmotivated. He is upset with his parents. As an only child, he feels pressured to succeed in business, but is hopeless about ever measuring up to their ambitions for him. He admits to relying on alcohol and marijuana daily for sleep initiation and anxiety management. When asked what would be most helpful to him, Jerry seems surprised by the question: “Everyone tells me that I have an attention problem; my roommate gave me Adderall, and it worked!”

The psychiatric conditions most frequently observed among college students are anxiety, depression, ADHD, substance abuse, and bipolar disorder. Eating disorders carry a high risk for medical comorbidity. Stress and anxiety may worsen during exam periods. Moreover, most psychiatric disorders have their onset during late adolescence and young adulthood. Students in crisis may present with suicidality or psychotic symptoms. Excessive use of alcohol and marijuana pose further health hazards.

When they hit a roadblock with their academic work students like Jerry, who initially reach out to the counseling service for urgent help, often request anxiolytic or stimulant medications for immediate relief. Emboldened by societal opinion and the stubbornly persistent urban myth that stimulants are “smart drugs,” students expect our assistance with cognitive enhancement to prevail in competitive contexts.

Studies estimate that about half of cases with childhood onset of ADHD persist into adulthood.1 However, because of the well-known rates of diversion and abuse, psychiatrists in college health services are wary of prescribing stimulants without a thorough diagnostic work-up.2 An in-depth psychiatric interview, screening with the Adult ADHD Self-Report Scale, and a referral for neuropsychological testing are recommended by a fair number of counseling services before any prescriptions for stimulants are issued. Ideally, the psychiatric work-up should include a basic medical exam, EKG, and routine lab testing. Students are also made aware of the university’s academic support resources.

Students who have come to rely on alcohol and marijuana during adolescence for alleviating anxiety, depression, self-esteem issues, camouflaging inter-personal conflict, and for fun are loath to give this up. They feel culturally emboldened to take advantage of the “medicinal” effects of the various marijuana strains. “I only smoke Blue Dreams,” Jerry announces, referring to a variety of marijuana high in cannabidiol content with purported anxiolytic properties.

How best to treat comorbid mood, anxiety, and substance use disorders has been the subject of a longstanding debate. A review of recent evidence-based studies recommends the integrated treatment of co-occurring mood and substance use disorders to achieve a superior outcome.3 The FDA has approved medications to address alcohol, opiate, and nicotine dependence, but the treatment for excessive marijuana use consists of psychosocial interventions.

Yet, psychiatrists should keep in mind that academic performance problems are a multifactorial phenomenon. They may be related to poor study habits, or academic under-preparedness. This can create a loss of confidence and narcissistic injury among competitive peers or result in oppositional behavior towards authority figures. There can be a lack of motivation because the student’s major was not his or her first choice. Students may be disappointed about not being accepted by their dream school and therefore not apply themselves.

Undergraduate students, in particular, face the difficult task of being away from home and adjusting to life on their own. Despite frequent electronic communication with parents and friends, they may be suffering from homesickness. Maintaining good self-care is surprisingly difficult to achieve. Sometimes the success or failure of the semester is in question because the student fails to establish a predictable sleep/wake cycle and get to class on time. Chronic sleep deprivation is a major contributor to lack of concentration and focus. Without the infrastructure their families provided, students need to learn to eat 3 nutritious meals a day rather than rely on unhealthy snacks. Similarly, in times of stress, it is a challenge to achieve a reasonable work/life balance and have time for leisure activities such as socialization with peers or exercise. Relationship difficulties and romantic disappointments loom large.

Back to Jerry, a fictionalized, albeit typical case. In the initial visit, the psychiatrist explores the nature of the concerns in a non-judgmental fashion, forms rapport with the student, and gains an understanding of his level of psychological maturity and ability to collaborate in making decisions about health care. Creating a shared language about what the basic issues are builds the foundation for a working alliance.

After meeting with the psychiatrist for several sessions, Jerry acknowledges his passion for creative writing. With encouragement, Jerry opens up to his parents. To his surprise, they respond supportively. His anxiety ebbs and he decreases his daily marijuana and alcohol consumption. He is discouraged from using his roommate’s Adderall. He agrees to a referral for CBT for anxiety and insomnia. Jerry’s parents are quite willing to participate in family sessions by conference call. The psychiatrist decides that treatment with medication does not seem necessary for now.

Dr. Kring is Associate Director, Psychiatry Services, Counseling and Wellness Services, New York University, NY.

-Dr. Kring acknowledges the contribution of the GAP Student Committee: Helene Keable, MD, Alexandra Ackerman MD, Malkah Notman, MD, and David Stern, MD.

 Faraone S, Biederman J, Spencer R, et al. Attention-deficit/hyperactivity disorder in adults: an overview. Biol Psychiatry. 2000 48:9-20.

 Prosek E, Giordano AL, Turner KD, et al. Prevalence and correlates of stimulant medication misuse among the collegiate population. J College Student Psychother. 2017. 

https://www.tandfonline.com/doi/abs/10.1080/87568225.2017.131369

 Pettinati HM, O’Brien CP, Dundon. Current status of co-occurring mood and substance use disorders: a new therapeutic target. Am J Psychiatry. 2013;170:23-30.

Emerging adults in the midst of a tremendous emotional growth spurt and a leap of neurocognitive maturation often need guidance articulating what bothers them.

College Students Under Stress

is Adjunct Professor of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD. He is also Former Chief, Experimental Therapeutics Branch, Intramural Research Program, NIMH, and Former Director, NIH Clinical Center 4-East Research Ward for Schizophrenia

The prevalence of schizophrenia in the US is 0.3%. Really? I thank the Treatment Advocacy Center and Dr. Fuller Torrey and Elizabeth Sinclair for bringing attention to the NIMH’s website, which states just that.

A schizophrenia prevalence of 1% of the US population is a foundation fact that has wide implications.

 Torrey and Sinclair discuss this odd error with characteristic pith and accuracy in the 

 The “disappearance” of 2 million patients with schizophrenia is certainly an effective way to bring home the implications of the NIMH error.

response of NIMH Director Dr. Joshua A. Gordon

 to Torrey and Sinclair’s piece does little to persuade that the NIMH is on point. Pardon this 21th century cynicism, but was there an interest in reporting a lower prevalence figure for the most serious of mental illnesses? Might a lower prevalence suggest that it is less a problem? That we have somehow been successful in reducing its occurrence?

The NIMH error is particularly noteworthy in light of recent Congressional efforts to bring attention to persons who suffer with serious mental illness. The Helping Families in Mental Health Crisis Act approved by the House in 2016 and later incorporated into the 21th Century Cures Act in 2017 highlighted the need for renewed, effective attention to this population by Federal agencies. Does NIMH research meet this challenge?

NIMH Intramural Research beds for schizophrenia at St. Elizabeth’s Hospital in Washington, DC and those at the NIH Clinical Center in Bethesda together numbered in the range of 35 to 45 in the 1970s through 1990s. Research into schizophrenia at the NIH Clinical Center today (there are no longer beds at St. Elizabeth’s Hospital) limps along with few inpatients and lacks supporting energy from “above.” Inpatient research beds represent a national resource for families of patients with schizophrenia. No one has used research beds better than The NCI in its Intramural Research Program.

The NIMH website highlights 2 clinical studies, CATIE and RAISE.CATIE, completed in the 1990s, brought home the fact the new generation of antipsychotic drugs is no more effective than older drugs, leaving clozapine, first used in the 1970s and FDA approved in 1989 for patients with treatment resistance as the only antipsychotic drug with enhanced efficacy. RAISE further demonstrates the limitation of current treatment. Unfortunately, the NIMH has never followed up its own leads to improve the treatment of schizophrenia. Dr. Gordon correctly mentions the importance of neurocognitive deficits of schizophrenia, an area pioneered by Intramural NIMH Clinical Scientists. Despite considerable academic and industry efforts, drug development for these deficits has been entirely unsuccessful. A fresh look is in order.

Perhaps just an oversight, the NIMH error about schizophrenia prevalence prompts a closer examination into NIMH’s attention to schizophrenia. I support the suggestion by Torrey and Sinclair for a new study of the prevalence of schizophrenia. It is also time for an independent review of the NIMH’s research efforts into our most serious mental illness.

Dr. Pickar reports no conflicts of interest concerning the subject matter of this article.

 Regier DA Narrow WE, Rae DS, et al. The de facto US mental and addictive disorders service system. 

Hocus Pocus: How the NIMH made 2 million people with schizophrenia disappear

 Gordon J. On the prevalence of schizophrenia-and on the NIMH. 

Might a lower prevalence suggest that it is less a problem?

The Prevalence of Schizophrenia in the US

Everyone in Puerto Rico (PR) was affected by Hurricane Maria, which made landfall on September 20, 2017 as the largest scale natural disaster in the US during our lifetime. Many months later, Puerto Ricans continue to face unreasonable obstacles that prevent recovery. This article summarizes literature on post-disaster mental health and describes the public health crisis in PR. Special attention is given to highlight higher suicide rates and PTSD that develop in post-disaster areas.

Psychosocial context and obstacles to recovery

This article summarizes literature on post-disaster mental health and describes the public health crisis in Puerto Rico. Special attention is given to highlight higher suicide rates and PTSD that develop in post-disaster areas.

Psychiatric Times Vol 35 No 4

Five Things to Know About Inflammation and Depression

Is PTSD a Systemic Disorder?

A “Sickness of Our Time”: How Suicide First Became a Research Question

College Students Under Stress

The Prevalence of Schizophrenia in the US

PTSD and Suicide After Natural Disasters

Birthday Party

Online Communities for Drug Withdrawal: What Can We Learn?

Lifeline for Pregnant and Postpartum Women Who Are Drowning in Plain Sight

What Psychiatrists Need to Know About the Determination of Dispositional Capacity