The revolution of personalized psychiatry: will technology make it happen sooner?

Personalized medicine (PM) aims to establish a new approach in clinical decision-making, based upon a patient's individual profile in order to tailor treatment to each patient's characteristics. Although this has become a focus of the discussion also in the psychiatric field, with evidence of its high potential coming from several proof-of-concept studies, nearly no tools have been developed by now that are ready to be applied in clinical practice. In this paper, we discuss recent technological advances that can make a shift toward a clinical application of the PM paradigm. We focus specifically on those technologies that allow both the collection of massive as much as real-time data, i.e., electronic medical records and smart wearable devices, and to achieve relevant predictions using these data, i.e. the application of machine learning techniques.

Differential functional connectivity within an emotion regulation neural network among individuals resilient and susceptible to the depressogenic effects of early life stress.

BACKGROUND: Early life stress (ELS) is a significant risk factor for depression. The effects of ELS exposure on neural network organization have not been differentiated from the effect of depression. Furthermore, many individuals exposed to ELS do not develop depression, yet the network organization patterns differentiating resiliency versus susceptibility to the depressogenic effects of ELS are not clear. METHOD: Women aged 18-44 years with either a history of ELS and no history of depression (n = 7), a history of ELS and current or past depression (n = 19), or a history of neither ELS nor depression (n = 12) underwent a resting-state 3-T functional magnetic resonance imaging (fMRI) scan. An emotion regulation brain network consisting of 21 nodes was described using graph analyses and compared between groups. RESULTS: Group differences in network topology involved decreased global connectivity and hub-like properties for the right ventrolateral prefrontal cortex (vlPFC) and decreased local network connectivity for the dorsal anterior cingulate cortex (dACC) among resilient individuals. Decreased local connectivity and increased hub-like properties of the left amygdala, decreased hub-like properties of the dACC and decreased local connectivity of the left vlPFC were observed among susceptible individuals. Regression analyses suggested that the severity of ELS (measured by self-report) correlated negatively with global connectivity and hub-like qualities for the left dorsolateral PFC (dlPFC). CONCLUSIONS: These preliminary results suggest functional neural connectivity patterns specific to ELS exposure and resiliency versus susceptibility to the depressogenic effects of ELS exposure.

Assessing in-session rumination and its effects on CBT for depression.

The study evaluated if rumination of patients during therapy (i.e., in-session rumination) relates to whether or not they do less well in CBT treatment. We developed a reliably assessed in-session rumination observational measure and evaluated its relationship to depression over the course of CBT. Rated sessions came from 63 treatment-naïve patients with major depressive disorder who participated in CBT in the PReDICT study (Dunlop et al., 2017). In-session rumination was operationalized as repetitive, negative, and passive talking about depressive topics. Trained undergraduates rated the intensity and duration of in-session rumination occurring during 57 initial therapy sessions (i.e., session one) and 45 sessions in the middle of treatment (i.e., session eight). The observational ratings were sufficiently reliable (all ICCs > 0.69). Mixed model results indicated that greater intensity of in-session rumination during the initial treatment session predicted higher levels of subsequent clinician-rated depressive symptoms (p < .023). Regression results indicated that greater intensity and duration of in-session rumination at session 8 significantly predicted higher clinician-rated symptoms at end of treatment (p's < 0.02). In-session rumination intensity and duration were not, however, related to subsequent self-reported depressive symptoms. The results support efforts to identify which patients might benefit from rumination-specific interventions.

Validity and severity thresholds for the depression subscale of the affective self rating scale: An equipercentile equating study using classical test theory.

BACKGROUND: The Affective Symptoms Scale (ASRS) is a unique instrument designed to separately measure depressive and manic symptoms in mood disorders. We validated the ASRS against the Patient Health Questionnaire (PHQ-9) and the Quick Inventory of Depressive Symptomatology (QIDS-16). METHODS: A retrospective study of 258 patients who completed the PHQ-9, QIDS-16 and ASRS as part of routine clinical care. To establish meaningful clinical thresholds for the depression subscale of the ASRS, it was equated with the QIDS and the PHQ-9. RESULTS: The depression subscale of the ASRS had significant positive correlations with the QIDS-16 and the PHQ-9 (respectively, r= 0.8, t[253] = 19.8, p < 0.001, and r= 0.8, t[245] = 28.2, p < 0.001). The equipercentile equating method with the PHQ-9 indicated that the thresholds corresponded to ASRS depression subscale scores of 5.4, 10.6, 16.1, and 23. Equating with the QIDS indicated that thresholds corresponded to ASRS depression subscale scores of 5.1, 11, 18.4, and 27.5. LIMITATIONS: Limitations include a small sample size that did not allow more detailed statistical analysis, such as Item Response Theory. The population is a heterogenous population at a university outpatient setting. CONCLUSIONS: The ASRS depression subscale significantly correlated with the PHQ-9 and QIDS-16. Our proposed threshold scores for the ASRS are 5, 11, 16 and 23 to indicated mild, moderate, severe and very severe depression respectively.

Citalopram plus low-dose pipamperone versus citalopram plus placebo in patients with major depressive disorder: an 8-week, double-blind, randomized study on magnitude and timing of clinical response.

BACKGROUND: Selective serotonin reuptake inhibitors take several weeks to achieve their full antidepressant effects. Post-synaptic 5-HT2A receptor activation is thought to be involved in this delayed therapeutic effect. Pipamperone acts as a highly selective 5-HT2A/D4 antagonist when administered in low doses. The purpose of this study was to compare citalopram 40 mg once daily plus pipamperone 5 mg twice daily (PipCit) versus citalopram plus placebo twice daily for magnitude and onset of therapeutic effect. METHOD: An 8-week, randomized, double-blind study in patients with major depressive disorder was carried out. RESULTS: The study population comprised 165 patients (citalopram and placebo, n=82; PipCit, n=83) with a mean baseline Montgomery-Asberg Depression Rating Scale (MADRS) score of 32.6 (s.d.=5.5). In the first 4 weeks, more citalopram and placebo than PipCit patients discontinued treatment (18% v. 4%, respectively, p=0.003). PipCit patients had significantly greater improvement in MADRS score at week 1 [observed cases (OC), p=0.021; last observation carried forward (LOCF), p=0.007] and week 4 (LOCF, p=0.025) but not at week 8 compared with citalopram and placebo patients. Significant differences in MADRS scores favoured PipCit in reduced sleep, reduced appetite, concentration difficulties and pessimistic thoughts. Mean Clinical Global Impression-Improvement scores were significantly improved after 1 week of PipCit compared with citalopram and placebo (OC and LOCF, p=0.002). CONCLUSIONS: Although the MADRS score from baseline to 8 weeks did not differ between groups, PipCit provided superior antidepressant effects and fewer discontinuations compared with citalopram and placebo during the first 4 weeks of treatment, especially in the first week.

The CRF system, stress, depression and anxiety-insights from human genetic studies.

A concatenation of findings from preclinical and clinical studies support a preeminent function for the corticotropin-releasing factor (CRF) system in mediating the physiological response to external stressors and in the pathophysiology of anxiety and depression. Recently, human genetic studies have provided considerable support to several long-standing hypotheses of mood and anxiety disorders, including the CRF hypothesis. These data, reviewed in this report, are congruent with the hypothesis that this system is of paramount importance in mediating stress-related psychopathology. More specifically, variants in the gene encoding the CRF(1) receptor interact with adverse environmental factors to predict risk for stress-related psychiatric disorders. In-depth characterization of these variants will likely be important in furthering our understanding of the long-term consequences of adverse experience.

Lower CSF oxytocin concentrations in women with a history of childhood abuse.

Early-life disruption of the parent-child relationship, for example, in the form of abuse, neglect or loss, dramatically increases risk for psychiatric, as well as certain medical, disorders in adulthood. The neuropeptide oxytocin (OT) plays a seminal role in mediating social affiliation, attachment, social support, maternal behavior and trust, as well as protection against stress and anxiety. We therefore examined central nervous system OT activity after early-life adversity in adult women. We measured OT concentrations in cerebrospinal fluid (CSF) collected from 22 medically healthy women, aged 18-45 years, categorized into those with none-mild versus those with moderate-severe exposure to various forms of childhood abuse or neglect. Exposure to maltreatment was associated with decreased CSF OT concentrations. A particularly strong effect was identified for emotional abuse. There were inverse associations between CSF OT concentrations and the number of exposure categories, the severity and duration of the abuse and current anxiety ratings. If replicated, the association of lower adult CSF OT levels with childhood trauma might indicate that alterations in central OT function may be involved in the adverse outcomes of childhood adversity.

Interactions between BDNF Val66Met polymorphism and early life stress predict brain and arousal pathways to syndromal depression and anxiety.

Individual risk markers for depression and anxiety disorders have been identified but the explicit pathways that link genes and environment to these markers remain unknown. Here we examined the explicit interactions between the brain-derived neurotrophic factor (BDNF) Val66Met gene and early life stress (ELS) exposure in brain (amygdala-hippocampal-prefrontal gray matter volume), body (heart rate), temperament and cognition in 374 healthy European volunteers assessed for depression and anxiety symptoms. Brain imaging data were based on a subset of 89 participants. Multiple regression analysis revealed main effects of ELS for body arousal (resting heart rate, P=0.005) and symptoms (depression and anxiety, P<0.001) in the absence of main effects for BDNF. In addition, significant BDNF-ELS interactions indicated that BDNF Met carriers exposed to greater ELS have smaller hippocampal and amygdala volumes (P=0.013), heart rate elevations (P=0.0002) and a decline in working memory (P=0.022). Structural equation path modeling was used to determine if this interaction predicts anxiety and depression by mediating effects on the brain, body and cognitive measures. The combination of Met carrier status and exposure to ELS predicted reduced gray matter in hippocampus (P<0.001), and associated lateral prefrontal cortex (P<0.001) and, in turn, higher depression (P=0.005). Higher depression was associated with poorer working memory (P=0.005), and slowed response speed. The BDNF Met-ELS interaction also predicted elevated neuroticism and higher depression and anxiety by elevations in body arousal (P<0.001). In contrast, the combination of BDNF V/V genotype and ELS predicted increases in gray matter of the amygdala (P=0.003) and associated medial prefrontal cortex (P<0.001), which in turn predicted startle-elicited heart rate variability (P=0.026) and higher anxiety (P=0.026). Higher anxiety was linked to verbal memory, and to impulsivity. These effects were specific to the BDNF gene and were not evident for the related 5HTT-LPR polymorphism. Overall, these findings are consistent with the correlation of depression and anxiety, yet suggest that partially differentiated gene-brain cognition pathways to these syndromes can be identified, even in a nonclinical sample. Such findings may aid establishing an evidence base for more tailored intervention strategies.

Continuous expression of corticotropin-releasing factor in the central nucleus of the amygdala emulates the dysregulation of the stress and reproductive axes.

An increase in corticotropin-releasing factor (CRF) is a putative factor in the pathophysiology of stress-related disorders. As CRF expression in the central nucleus of the amygdala (CeA) is important in adaptation to chronic stress, we hypothesized that unrestrained synthesis of CRF in CeA would mimic the consequences of chronic stress exposure and cause dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, increase emotionality and disrupt reproduction. To test this hypothesis, we used a lentiviral vector to increase CRF-expression site specifically in CeA of female rats. Increased synthesis of CRF in CeA amplified CRF and arginine vasopressin peptide concentration in the paraventricular nucleus of the hypothalamus, and decreased glucocorticoid negative feedback, both markers associated with the pathophysiology of depression. In addition, continuous expression of CRF in CeA also increased the acoustic startle response and depressive-like behavior in the forced swim test. Protein levels of gonadotropin-releasing hormone in the medial preoptic area were significantly reduced by continuous expression of CRF in CeA and this was associated with a lengthening of estrous cycles. Finally, sexual motivation but not sexual receptivity was significantly attenuated by continuous CRF synthesis in ovariectomized estradiol-progesterone-primed females. These data indicate that unrestrained CRF synthesis in CeA produces a dysregulation of the HPA axis, as well as many of the behavioral, physiological and reproductive consequences associated with stress-related disorders.Molecular Psychiatry (2009) 14, 37-50; doi:10.1038/mp.2008.91; published online 12 August 2008.

Cholecystokinin inhibits tail pinch-induced eating in rats.

Peripheral administration of the COOH-terminal octapeptide of cholecystokinin in doses from 1 to 100 micrograms per kilogram of body weight (0.25 to 25.0 micrograms per rat) significantly antagonized tail pinch-induced eating in rats, an animal model for stress-induced human hyperphagia. Centrally administered cholecystokinin was effective only in high doses (3 micrograms into the cerebral ventricle). The finding that the minimal effective dose of cholecystokinin in suppressing stress-induced appetitive behavior is smaller after peripheral than central administration suggests that the peptide is acting on peripheral, as opposed to central nervous system, substrates.

Regional brain concentrations of neuropeptides in Huntington's chorea and schizophrenia.

To ascertain whether Huntington's chorea and schizophrenia are associated with specific regional alterations in neurotensin, somatostatin, and thyrotropin-releasing hormone, the concentrations of these putative neurotransmitters were measured by radioimmunoassay in postmortem brain samples from patients with Huntington's chorea or schizophrenia. Compared to 50 patients without psychiatric or neurological disease, the patients with Huntington's chorea showed significantly elevated concentrations of all three neuropeptides in the nucleus caudatus. In the nucleus accumbens somatostatin levels were increased threefold, while in the amygdala thyrotropin-releasing hormone levels were elevated. In contrast, the schizophrenics exhibited reduced levels of thyrotropin-releasing hormone in two frontal cortical regions, reduced somatostatin levels in one frontal cortical area, and increased neurotensin levels in one frontal cortical area. None of the differences between the diseased brains and the controls could be accounted for by differences in age, sex, or time between death and autopsy.

Elevated concentrations of CSF corticotropin-releasing factor-like immunoreactivity in depressed patients.

The possibility that hypersecretion of corticotropin-releasing factor (CRF) contributes to the hyperactivity of the hypothalamo-pituitary-adrenal axis observed in patients with major depression was investigated by measuring the concentration of this peptide in cerebrospinal fluid of normal healthy volunteers and in drug-free patients with DSM-III diagnoses of major depression, schizophrenia, or dementia. When compared to the controls and the other diagnostic groups, the patients with major depression showed significantly increased cerebrospinal fluid concentrations of CRF-like immunoreactivity; in 11 of the 23 depressed patients this immunoreactivity was greater than the highest value in the normal controls. These findings are concordant with the hypothesis that CRF hypersecretion is, at least in part, responsible for the hyperactivity of the hypothalamo-pituitary-adrenal axis characteristic of major depression.

Overexpression of the high affinity choline transporter in cortical regions affected by Alzheimer's disease. Evidence from rapid autopsy studies.

Cholinergic deficits in Alzheimer's disease are typically assessed by choline acetyltransferase, the enzyme that synthesizes acetylcholine. However, the determining step in acetylcholine formation is choline uptake via a high affinity transporter in nerve terminal membranes. Evaluating uptake is difficult because regulatory changes in transporter function decay rapidly postmortem. To overcome this problem, brain regions from patients with or without Alzheimer's disease were frozen within 4 h of death and examined for both choline acetyltransferase activity and for binding of [3H]-hemicholinium-3 to the choline transporter. Consistent with the loss of cholinergic projections, cerebral cortical areas exhibited marked decreases in enzyme activity whereas the putamen, a region not involved in Alzheimer's disease, was unaffected. However, [3H]hemicholinium-3 binding was significantly enhanced in the cortical regions. In the frontal cortex, the increase in [3H]hemicholinium-3 binding far exceeded the loss of choline acetyltransferase, indicating transporter overexpression beyond that necessary to offset loss of synaptic terminals. These results suggest that, in Alzheimer's disease, the loss of cholinergic function is not dictated simply by destruction of nerve terminals, but rather involves additional alterations in choline utilization; interventions aimed at increasing the activity of cholinergic neurons may thus accelerate neurodegeneration.

Neurobiology of posttraumatic stress disorder.

Recent advances on the neurobiology of posttraumatic stress disorder include: the utilization of functional brain imaging; the incorporation of cross-system research including neuroendocrine (hypothalamic-pituitary-adrenal and hypothalamic-pituitary-thyroid axes), neurochemical (corticotropin-releasing factor, norepinephrine, serotonin, endogenous opiates), and neuroimmunological (humoral and cellular immunity) systems; the expansion beyond exclusive study of combat veterans to include posttraumatic stress disorder patients suffering from noncombat traumas; and the development of animal models of traumatic stress.

Childhood trauma predicts antidepressant response in adults with major depression: data from the randomized international study to predict optimized treatment for depression.

Few reliable predictors indicate which depressed individuals respond to antidepressants. Several studies suggest that a history of early-life trauma predicts poorer response to antidepressant therapy but results are variable and limited in adults. The major goal of the present study was to evaluate the role of early-life trauma in predicting acute response outcomes to antidepressants in a large sample of well-characterized patients with major depressive disorder (MDD). The international Study to Predict Optimized Treatment for Depression (iSPOT-D) is a randomized clinical trial with enrollment from December 2008 to January 2012 at eight academic and nine private clinical settings in five countries. Patients (n=1008) meeting DSM-IV criteria for MDD and 336 matched healthy controls comprised the study sample. Six participants withdrew due to serious adverse events. Randomization was to 8 weeks of treatment with escitalopram, sertraline or venlafaxine with dosage adjusted by the participant's treating clinician per routine clinical practice. Exposure to 18 types of traumatic events before the age of 18 was assessed using the Early-Life Stress Questionnaire. Impact of early-life stressors-overall trauma 'load' and specific type of abuse-on treatment outcomes measures: response: (⩾50% improvement on the 17-item Hamilton Rating Scale for Depression, HRSD17 or on the 16-item Quick Inventory of Depressive Symptomatology-Self-Rated, QIDS_SR16) and remission (score ⩽7 on the HRSD17 and ⩽5 on the QIDS_SR16). Trauma prevalence in MDD was compared with controls. Depressed participants were significantly more likely to report early-life stress than controls; 62.5% of MDD participants reported more than two traumatic events compared with 28.4% of controls. The higher rate of early-life trauma was most apparent for experiences of interpersonal violation (emotional, sexual and physical abuses). Abuse and notably abuse occurring at ⩽7 years of age predicted poorer outcomes after 8 weeks of antidepressants, across the three treatment arms. In addition, the abuses occurring between ages 4 and 7 years differentially predicted the poorest outcome following the treatment with sertraline. Specific types of early-life trauma, particularly physical, emotional and sexual abuse, especially when occurring at ⩽7 years of age are important moderators of subsequent response to antidepressant therapy for MDD.

Chronic administration of the triazolobenzodiazepine alprazolam produces opposite effects on corticotropin-releasing factor and urocortin neuronal systems.

In view of the substantial preclinical evidence that supports a seminal role of central corticotropin-releasing factor (CRF) neuronal systems in the physiology and pathophysiology of stress and anxiety, it is reasonable to suggest that the anxiolytic properties of benzodiazepines are mediated, at least in part, via regulation of CRFergic function. To begin to test this complex hypothesis, we examined the effects of acute and chronic administration of the triazolobenzodiazepine agonist alprazolam on CRF peptide concentrations, receptor-binding density, and mRNA expression in the CNS. Additionally, we measured mRNA expression for urocortin, a recently discovered neuropeptide that is generally considered to be a second endogenous ligand for CRF receptors. Both acute and chronic alprazolam administration was found to decrease CRF concentrations within the locus coeruleus. Furthermore, chronic alprazolam decreased basal activity of the hypothalamic-pituitary-adrenal axis, CRF mRNA expression in the central nucleus of the amygdala, and CRF(1) mRNA expression and receptor binding in the basolateral amygdala. In marked contrast, urocortin mRNA expression in the Edinger-Westphal nucleus and CRF(2A) receptor binding in the lateral septum and ventromedial hypothalamus were increased. Similar findings of an inverse relationship between the CRF(1) and CRF(2A) receptor systems have been reported in an anxiety model based on adverse early-life experience, suggesting the intriguing possibility that CRF neuronal systems may be comprised of two separate, but interrelated, subdivisions that can be coordinately and inversely regulated by stress, anxiety, or anxiolytic drugs.

Enhanced neurotensin neurotransmission is involved in the clinically relevant behavioral effects of antipsychotic drugs: evidence from animal models of sensorimotor gating.

To date, none of the available antipsychotic drugs are curative, all have significant side-effect potential, and a receptor-binding profile predictive of superior therapeutic ability has not been determined. It has become increasingly clear that schizophrenia does not result from the dysfunction of a single neurotransmitter system, but rather from an imbalance between several interacting systems. Targeting neuropeptide neuromodulator systems that concertedly regulate all affected neurotransmitter systems could be a promising novel therapeutic approach for schizophrenia. A considerable database is concordant with the hypothesis that antipsychotic drugs act, at least in part, by increasing the synthesis and release of the neuropeptide neurotensin (NT). In this report, we demonstrate that NT neurotransmission is critically involved in the behavioral effects of antipsychotic drugs in two models of antipsychotic drug activity: disrupted prepulse inhibition of the acoustic startle response (PPI) and the latent inhibition (LI) paradigm. Blockade of NT neurotransmission using the NT receptor antagonist 2-[[5-(2,6-dimethoxyphenyl)-1-(4-(N-(3-dimethylaminopropyl)-N-methylcarbamoyl)-2-isopropylphenyl)-1H- pyrazole-3-carbonyl]-amino]-adamantane-2-carboxylic acid, hydrochloride (SR 142948A) prevented the normal acquisition of LI and haloperidol-induced enhancement of LI. In addition, SR 142948A blocked the PPI-restoring effects of haloperidol and the atypical antipsychotic drug quetiapine in isolation-reared animals deficient in PPI. We also provide evidence of deficient NT neurotransmission as well as a left-shifted antipsychotic drug dose-response curve in isolation-reared rats. These novel findings, together with previous observations, suggest that neurotensin receptor agonists may represent a novel class of antipsychotic drugs.

Peptides and psychoneuroendocrinology. A perspective.

Research indicates that brain peptides exert both behavioral and endocrinologic effects in humans and animals. This review summarizes the best known behavioral actions of four endogenous peptides: luteinizing hormone-releasing hormone (LHRH), adrenocorticotrophic hormone (ACTH), vasopressin, and angiotensin. The hypothalamic-releasing hormones play a role in modulating pituitary-end organ systems. Behavioral disorders may, in the future, be susceptible to formulation in terms of changes in brain peptides. Peptide research in psychiatry may be approached in several ways.

The relationship of depression to cardiovascular disease: epidemiology, biology, and treatment.

This article reviews the burgeoning literature on the relationship of mood disorders and heart disease. Major depression and depressive symptoms, although commonly encountered in medical populations, are frequently underdiagnosed and undertreated in patients with cardiovascular disease (CVD). This is of particular importance because several studies have shown depression and its associated symptoms to be a major risk factor for both the development of CVD and death after an index myocardial infarction. This review of the extant literature is derived from MEDLINE searches (1966-1997) using the search terms "major depression," "psychiatry," "cardiovascular disease," and "pathophysiology." Studies investigating pathophysiological alterations related to CVD in depressed patients are reviewed. The few studies on treatment of depression in patients with CVD are also described. Treatment of depression in patients with CVD improves their dysphoria and other signs and symptoms of depression, improves quality of life, and perhaps even increases longevity. Recommendations for future research are proposed.