Promoter methylation of the glucocorticoid receptor following trauma may be associated with subsequent development of PTSD.

OBJECTIVES: The ability to identify persons at elevated risk for post-traumatic stress disorder (PTSD) soon after exposure to trauma, could aid clinical decision-making and treatment. In this study, we explored whether cytosine methylation of the 1 F promoter of the NR3C1 (glucocorticoid receptor [GR]) gene obtained immediately following a trauma could predict PTSD. METHODS: Our sample comprised 52 trauma survivors (28 women, 24 men), presenting to the Emergency Department (ED) within six hours of a traumatic event and followed for 13 months. Blood samples were taken at intake (n = 42) and again at the end of the study (13 months later, n = 27) to determine NR3C1-1F promoter methylation as well as plasma levels of cortisol, adrenocorticotropic-hormone (ACTH), and neuropeptide-Y (NPY). RESULTS: At the 13-month follow-up, participants who met the PTSD criteria (n = 4) showed significantly lower NR3C1-1F promoter sum percent methylation compared to the non-PTSD group (n = 38). Further, NR3C1-1F methylation at ED intake was inversely correlated with PTSD severity 13 months later, indicating that lower NR3C1-1F promoter methylation in the immediate aftermath of trauma was associated with the development of PTSD. CONCLUSION: To the extent that reduced promoter methylation is associated with greater GR expression and responsivity, this finding is consistent with the hypothalamic-pituitary-adrenal dysregulation previously described for PTSD.

Hydrocortisone in the emergency department: a prospective, double-blind, randomized, controlled posttraumatic stress disorder study. Hydrocortisone during golden hours.

OBJECTIVES: A blunted response of the hypothalamic-pituitary-adrenal axis immediately after exposure to traumatic events has been proposed as a risk factor for posttraumatic stress disorder (PTSD). Accordingly, administration of hydrocortisone in the aftermath of a traumatic event is indicated. This study consisted of a randomized, placebo-controlled, double-blind trial investigating whether a single intravenous dose of hydrocortisone administered within 6 hours after exposure to trauma would reduce the incidence of PTSD at the 13-month follow-up. METHODS: A total of 118 consented patients with acute stress symptoms were administered a single intravenous bolus of hydrocortisone/placebo within 6 hours of the traumatic event. Blood samples were taken before hydrocortisone administration. RESULTS: At 13 months, the hydrocortisone group did not differ from the placebo group regarding PTSD prevalence or symptom severity. However, a significant interaction between time of the trauma (ie, night, when cortisol's level is low) and treatment was found. Specifically, a lower prevalence of PTSD was found at the 13-month follow-up in the hydrocortisone night group. CONCLUSIONS: Administration of hydrocortisone within 6 hours of the traumatic event was not effective in preventing PTSD compared to placebo. However, nocturnal administration (when cortisol levels are low) may suggest a new venue for research.

Comparable reliability and acceptability of telepsychiatry and face-to-face psychiatric assessments in the emergency room setting.

OBJECTIVE: This study aims to compare the reliability and acceptability of psychiatric interviews using telepsychiatry and face-to-face modalities in the emergency room setting. METHODS: In this prospective observational feasibility study, psychiatric patients (n = 38) who presented in emergency rooms between April and June 2020, went through face-to-face and videoconference telepsychiatry interviews in a non-randomised varying order. Interviewers and a senior psychiatry resident who observed both interviews determined diagnosis, recommended disposition and indication for involuntary admission. Patients and psychiatrists completed acceptability post-assessment surveys. RESULTS: Agreement between raters on recommended disposition and indication for involuntary admission as measured by Cohen's kappa was 'strong' to 'almost perfect' (0.84/0.81, 0.95/0.87 and 0.89/0.94 for face-to-face vs. telepsychiatry, observer vs. face-to-face and observer vs. telepsychiatry, respectively). Partial agreement between the raters on diagnosis was 'strong' (Cohen's kappa of 0.81, 0.85 and 0.85 for face-to-face vs. telepsychiatry, observer vs. face-to-face and observer vs. telepsychiatry, respectively).Psychiatrists' and patients' satisfaction rates, and psychiatrists' perceived certainty rates, were comparably high in both face-to-face and telepsychiatry groups. CONCLUSIONS: Telepsychiatry is a reliable and acceptable alternative to face-to-face psychiatric assessments in the emergency room setting. Implementing telepsychiatry may improve the quality and accessibility of mental health services.Key pointsTelepsychiatry and face-to-face psychiatric assessments in the emergency room setting have comparable reliability.Patients and providers report a comparable high level of satisfaction with telepsychiatry and face-to-face modalities in the emergency room setting.Providers report a comparable level of perceived certainty in their clinical decisions based on telepsychiatry and face-to-face psychiatric assessments in the emergency room setting.

Neuroplasticity and second messenger pathways in antidepressant efficacy: pharmacogenetic results from a prospective trial investigating treatment resistance.

Genes belonging to neuroplasticity, monoamine, circadian rhythm, and transcription factor pathways were investigated as modulators of antidepressant efficacy. The present study aimed (1) to replicate previous findings in an independent sample with treatment-resistant depression (TRD), and (2) to perform a pathway analysis to investigate the possible molecular mechanisms involved. 220 patients with major depressive disorder who were non-responders to a previous antidepressant were treated with venlafaxine for 4-6 weeks and in case of non-response with escitalopram for 4-6 weeks. Symptoms were assessed using the Montgomery Asberg Depression Rating Scale. The phenotypes were response and remission to venlafaxine, non-response (TRDA) and non-remission (TRDB) to neither venlafaxine nor escitalopram. 50 tag SNPs in 14 genes belonging to the pathways of interest were tested for association with phenotypes. Molecular pathways (KEGG database) that included one or more of the genes associated with the phenotypes were investigated also in the STAR*D sample. The associations between ZNF804A rs7603001 and response, CREB1 rs2254137 and remission were replicated, as well as CHL1 rs2133402 and lower risk of TRD. Other CHL1 SNPs were potential predictors of TRD (rs1516340, rs2272522, rs1516338, rs2133402). The MAPK1 rs6928 SNP was consistently associated with all the phenotypes. The protein processing in endoplasmic reticulum pathway (hsa04141) was the best pathway that may explain the mechanisms of MAPK1 involvement in antidepressant response. Signals in genes previously associated with antidepressant efficacy were confirmed for CREB1, ZNF804A and CHL1. These genes play pivotal roles in synaptic plasticity, neural activity and connectivity.

The impact of serotonin receptor 1A and 2A gene polymorphisms and interactions on suicide attempt and suicide risk in depressed patients with insufficient response to treatment--a European multicentre study.

So far, associations between serotonergic neurotransmission pathways and suicidality have been reported. The aim of our study was to investigate the role of genetic polymorphisms and gene-gene interactions of the 5-HTR1A and the 5-HTR2A gene on suicide risk and/or a personal history of suicide attempts. A total of 374 major depressive disorder patients, adequately treated with antidepressants for at least 4 weeks, were collected in the context of a European multicentre study on treatment-resistant depression. We assessed suicidality using the Mini International Neuropsychiatric Interview and the Hamilton Rating Scale for Depression (HAM-D). Treatment response was defined as HAM-D ≤ 17 and remission as HAM-D ≤ 7 after 4 weeks of adequate antidepressant treatment. The 5-HTR1A rs6295 (C-1019G) single nucleotide polymorphism (SNP) and the 5-HTR2A rs7997012, rs6313, rs643627 and rs17288723 SNPs were selected for genotyping. Using logistic regression analyses, no association (P<0.05) could be found between any SNP and neither suicide risk nor personal history of suicide attempts. Interactions between 5HTR1A rs6295 and 5HTR2A rs6313 in suicide risk, and 5HTR1A rs6295 and 5HTR2A rs643627 in a personal history of suicide attempts have been reported (P=0.027 and 0.036, respectively); however, the results did not survive multiple testing correction. In conclusion, our study shows no association between 5HTR1A or 5HTR2A gene polymorphisms and both current suicide risk and personal history of suicide attempts. In addition, epistatic effects of 5HTR1A and 5HTR2A genes on suicidal behaviour were not significant, although sample size limitations do not allow definitive conclusions.

What to expect from a third step in treatment resistant depression: A prospective open study on escitalopram.

OBJECTIVES: Only few studies investigated treatment strategies for treatment resistant depression (TRD). The objective of this multicentre study was to evaluate TRD patients who did not respond to at least two antidepressants. METHODS: A total of 417 patients, who failed to respond to a previous retrospectively assessed antidepressant (AD1), were firstly included in a 6-week venlafaxine treatment (AD2); secondly, those who failed to respond were treated for further 6 weeks with escitalopram (AD3). RESULTS: Out of 417 patients who had failed to respond to previous treatment (AD1), 334 completed treatment with venlafaxine to prospectively define TRD. In the intent to treat (ITT) population in the first phase of the trial (AD2), responders to venlafaxine were 151 (36.21%) out of which remitters were 83 (19.90%). After phase one, 170 non-responders, defined as TRD, were included in the second phase and 157 completed the course. Of the 170 ITT entering the second phase (AD3), responders to escitalopram were 71 (41.76%) out of which remitters were 39 (22.94%). After the third treatment, patients showed a dropout rate of 7.65% and a rate of presence of at least one serious adverse event of 19.18%. CONCLUSIONS: Relevant rates of response and remission may be observed after a third line treatment in patients resistant to two previous treatments. A relevant limitation of this study was represented by the design: naturalistic, non-randomized, open-label, without a control sample and with unblinded raters.

Treatment with Ziprasidone for schizophrenia patients with OCD.

Comorbidity of obsessive-compulsive disorder (OCD) has been observed in about 15% of schizophrenic patients and has been associated with poor prognosis. Therefore, there is a need for specific treatment options for these patients (schizo-obsessive, ScOCD). This is an open, prospective study, aiming to test the efficacy of Ziprasidone (80-200mg/d) in ScOCD patients and comparing the response to the treatment between stable schizophrenic (N=16) and stable ScOCD (N=29) patients. Treatment effect with Ziprasidone was different in schizophrenic patients when stratified based on OCD comorbidity. Overall, the effect on OCD symptoms (as measured by the Yale Brown Obsessive Compulsive Scale, YBOCS) was found to be bimodal-either no response or exacerbation (for 45% of the patients, n=13) or significant improvement of symptoms (55%, n=16). Those who improved in OCD symptoms, improved also in negative and general schizophrenia symptoms, while ScOCD-unimproved group worsened in all symptoms. Whereas schizophrenic patients without OCD responded in a modest Gaussian distribution, they improved in schizophrenia negative symptoms and in general anxiety. This data suggests that schizo-obsessive disorder is a distinct and complex condition with more than one underlying pathogenesis. Definition of these ScOCD subgroups defined by their response to Ziprasidone might contribute to personalized medicine within the OCD-schizophrenia spectrum. Moreover, this finding suggests that ScOCD may be considered as a special schizophrenic subtype and its inclusion in schizophrenia treatment studies need to be further explored due to its divergent response.

Comorbidity in obsessive-compulsive disorder (OCD): a report from the International College of Obsessive-Compulsive Spectrum Disorders (ICOCS).

BACKGROUND: Obsessive-compulsive disorder (OCD) is often associated with significant psychiatric comorbidity. Comorbid disorders include mood and anxiety disorders as well as obsessive-compulsive spectrum disorders (OCSDs). This paper aims to investigate comorbidity of DSM Axis I-disorders, including OCSDs, in patients with OCD from 10 centers affiliated with the International College of Obsessive-Compulsive Spectrum Disorders (ICOCS). METHODS: This is a cross-sectional study of comorbidity of Axis I disorders including OCSDs in 457 outpatients with primary OCD (37% male; 63% female), with ages ranging from 12 to 88years (mean: 39.8±13). Treating clinicians assessed Axis I disorders using the Mini International Neuropsychiatric Interview and assessed OCSDs using the Structured Clinical Interview for OCD related/spectrum disorders (SCID-OCSD). RESULTS: In terms of the OCSDs, highest comorbidity rates were found for tic disorder (12.5%), BDD (8.71%) and self-injurious behavior (7.43%). In terms of the other Axis I-disorders, major depressive disorder (MDD; 15%), social anxiety disorder (SAD; 14%), generalized anxiety disorder (GAD; 13%) and dysthymic disorder (13%) were most prevalent. DISCUSSION: High comorbidity of some OCSDs in OCD supports the formal recognition of these conditions in a separate chapter of the nosology. Rates of other Axis I disorders are high in both the general population and in OCSDs, indicating that these may often also need to be the focus of intervention in OCD.

The different faces of Creutzfeldt-Jacob disease CJD in psychiatry.

OBJECTIVE: Creutzfeldt-Jacob Disease (CJD) is a rapidly progressive spongiform disease of the central nervous system. Psychiatric symptoms, though considered rare, can be the presenting symptoms of CJD and impose diagnosis difficulties. We reviewed prospectively our database to identify the frequency of psychiatric symptoms as identifying symptoms among our community. METHODS: We included all patients in Sheba Medical Center who were diagnosed with CJD between the years 2006 and 2012. Data were collected retrospectively. RESULTS: Twenty-three patients with CJD were admitted to our hospital during this 6-year period. Among them, 10 (44%) were diagnosed first as "psychiatric patients" due to psychiatric presenting symptoms. CONCLUSION: In our series, the frequency of misleading psychiatric symptom was 44%. Clinicians should therefore include CJD in their differential diagnoses of new onset dementia, particularly when associated psychosis and depression symptoms persist and worsen, despite standard psychiatric treatments.

Immediate ketamine treatment does not prevent posttraumatic stress responses in an animal model for PTSD.

Clinical studies suggest that administration of ketamine hydrochloride-an antagonist at the N-methyl-d-aspartate ionophore-provides short-term amelioration for depressive symptoms. The effects of a brief course of ketamine given immediately following exposure to psychogenic stress on the behavioral stress responses were assessed in an animal model of posttraumatic stress disorder. Animals exposed to stress were treated 1h later with ketamine (0.5, 5, and 15 mg/kg) or vehicle for three days (N = 107). Outcome measures included behavior in the elevated plus maze (EPM) and acoustic startle response (ASR) tests 30 days after initial exposure and freezing behavior upon exposure to a trauma-cue on day 31. Pre-set cut-off behavioral criteria classified exposed animals according to their EPM and ASR response-patterns into "extreme," "minimal," or "partial" behavioral response for analysis of prevalence rates of "PTSD-like behavior." Circulating corticosterone levels were assessed 20 min after injection of ketamine in exposed and unexposed animals (N = 62). The dexamethasone suppression test was used to assess negative feedback inhibition of the HPA axis. Prevalence rates of extremely-, partially-, or minimally-disrupted behavior demonstrated that ketamine administered immediately following stress exposure was ineffective in alleviating "PTSD-like behavior" at day 30 after exposure. Administration of ketamine was associated with increase in freezing behavior after exposure to a trauma-cue on day 31. Corticosterone levels were significantly suppressed by ketamine only in the exposed animals. Administration of ketamine immediately following trauma-exposure may not only be ineffective but actually detrimental in the long term. A disruption of the post-stress HPA-response has been raised as a contributing factor.

Evaluation of the role of MAPK1 and CREB1 polymorphisms on treatment resistance, response and remission in mood disorder patients.

Treatment resistant depression (TRD) is a significant clinical and public health problem. Among others, neuroplasticity and inflammatory pathways seem to play a crucial role in the pathomechanisms of antidepressant efficacy. The primary aim of this study was to investigate whether a set of single nucleotide polymorphisms (SNPs) within two genes implicated in neuroplasticity and inflammatory processes (the mitogen activated protein kinase 1, MAPK1 (rs3810608, rs6928, rs13515 and rs8136867), and the cyclic AMP responsive element binding protein 1, CREB1 (rs889895, rs6740584, rs2551922 and rs2254137)) was associated with antidepressant treatment resistance (according to two different definitions), in 285 Major Depressive Disorder (MDD) patients. As secondary aims, we investigated the genetic modulation of the same SNPs on response, remission and other clinical features both in MDD patients and in a larger sample including 82 Bipolar Disorder (BD) patients as well. All patients were screened in the context of a European multicenter project. No association between both the investigated genes and treatment resistance and response was found in MDD patients. However, considering remission, higher rates of CREB1 rs889895 GG genotype were reported in MDD patients. Moreover, MAPK1 rs8136867 AG genotype was found to be associated with remission in the whole sample (MDD and BD). Present results suggest that some genetic polymorphisms in both CREB1 and MAPK1 could be associated with treatment remission. Although further research is needed to draw more definitive conclusions, such results are intriguing since suggest a potential role of two genes implicated in neuroplasticity and inflammatory processes in symptom remission after antidepressant treatment.

The impact of Cytochrome P450 CYP1A2, CYP2C9, CYP2C19 and CYP2D6 genes on suicide attempt and suicide risk-a European multicentre study on treatment-resistant major depressive disorder.

Recently published data have reported associations between cytochrome P450 metabolizer status and suicidality. The aim of our study was to investigate the role of genetic polymorphisms of the cytochrome P450 genes on suicide risk and/or a personal history of suicide attempts. Two hundred forty-three major depressive disorder patients were collected in the context of a European multicentre resistant depression study and treated with antidepressants at adequate doses for at least 4 weeks. Suicidality was assessed using the Mini International Neuropsychiatric Interview and the Hamilton Rating Scale for Depression (HAM-D). Treatment response was defined as HAM-D ≤ 17 and remission as HAM-D ≤ 7 after 4 weeks of treatment with antidepressants at adequate dose. Genotyping was performed for all relevant variations of the CYP1A2 gene (*1A, *1F, *1C, *1 J, *1 K), the CYP2C9 gene (*2, *3), the CYP2C19 gene (*2, *17) and the CYP2D6 gene (*3, *4, *5, *6, *9, *19, *XN). No association between both suicide risk and personal history of suicide attempts, and the above mentioned metabolic profiles were found after multiple testing corrections. In conclusion, the investigated cytochrome gene polymorphisms do not seem to be associated with suicide risk and/or a personal history of suicide attempts, though methodological and sample size limitations do not allow definitive conclusions.

New insights into secondary prevention in post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) is unique amongst psychiatric disorders in two ways. Firstly, there is usually a very clear point of onset- the traumatic event The second unique feature of PTSD is that it is characterized by a failure of the normal response to resolve. Given these two characteristics, PTSD appears a good candidate for secondary prevention, ie, interventions immediately after the trauma. Evidence available starting from current concepts and contemporary research of potential secondary prevention interventions are presented. Common practices in the aftermath of trauma such as debriefing and benzodiazepines need to be carefully considered, taking into account their potential harm to the spontaneous recovery process, and the trajectory of PTSD, and not only judging them according to their immediate (comforting) effects. A discussion of the balance required between aiding recovery but not interfering with the potent natural resolution of symptoms (that is expected in most cases), along with potential avenues of future research, are presented. Results of a small pilot study with a single intervention of hydrocortisone immediately after trauma appear to be promising, and clearly indicate the need for further studies.

Pharmacological management of treatment-resistant obsessive-compulsive disorder.

Once considered rare and resistant to treatment, obsessive-compulsive disorder (OCD) has now emerged as a common, yet often unrecognized, psychiatric condition. Treatment with selective serotonin reuptake inhibitors (SSRIs) is effective in 40-60% of patients with OCD. Management of the remaining 40-60% of patients with treatment-resistant OCD is challenging. We review up-to-date evidence focusing on strategies for treatment-resistant OCD, including increasing the dose of SSRI, switching to another SSRI, augmentation with antipsychotics, and the use of serotonin noradrenaline (norepinephrine) reuptake inhibitors (SNRIs) and monoamine oxidase inhibitors (MAOIs). Finally, we provide a flow chart, which includes nonpharmacological interventions such as cognitive-behavioural therapy, family interventions and physical interventions such as neurosurgery and deep brain stimulation, alongside the pharmacological strategies.

Can posttraumatic stress disorder be prevented?

After trauma, it is often possible to prevent, or at least reduce the effect of, certain medical sequelae if intervention occurs within a particular time period: "the golden hour(s)". The possibility of a similar window of opportunity in posttraumatic stress disorder (PTSD) is discussed here. The essence of acute distress management should be to help contain and attenuate emotional reaction, and to encourage a return to full function and activity. Early intervention at this point could prevent the subsequent development of PTSD. Preclinical and clinical data suggest that amnesia of the traumatic event is associated with a decreased prevalence of PTSD, and that debriefing is not necessarily beneficial. Randomized, placebo-controlled studies are needed in order to examine what psychological and/or pharmacological interventions should or should not be made during the "golden hours" following trauma.

Post-traumatic stress disorder: facts and fiction.

PURPOSE OF REVIEW: This review provides an update on contemporary perspectives on post-traumatic stress disorder and challenges myths about the disorder and its treatment. Post-traumatic stress disorder has recently attracted public attention because of the impact of international terrorism, although the vast majority of post-traumatic stress disorder cases actually relate to civilian events such as car accidents, rape and violent robbery. This disorder requires deeper understanding and consensus among professionals. RECENT FINDINGS: Advances have been made in elucidating the neurobiology of this disorder, partly by using an animal model of post-traumatic stress disorder. Recent studies have focused on memory processes and the therapeutic role played by plasticity of the hypothalamic-pituitary-adrenal axis, and how this fits (or does not fit) in with the current therapeutic interventions. Guidelines have been established by various bodies in an attempt to streamline treatment options. SUMMARY: Understanding of post-traumatic stress disorder is incomplete. Future research should attempt to determine what treatments given during the 'window of opportunity' - the time from exposure until post-traumatic stress disorder develops - are effective. Care should be taken not to interfere with spontaneous recovery.