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Over the past 20 years, levels of Δ9-tetrahydrocannabinol (THC) in cannabis have significantly increased, while levels of cannabidiol (CBD) have increased much less in comparison. Cannabis with higher THC potency (commonly assessed via THC:CBD ratio) may increase the risk for cannabis dependence and trigger/exacerbate anxiety. However, few studies of cannabis potency effects on cannabis dependence and anxiety have examined gender moderation. Additionally, there are issues with how cannabis potency is calculated via the THC:CBD ratio that may contribute to inconsistencies in the literature. N = 202 (55.8 % women) recent cannabis users (>1 g in the past month) with trauma histories - a group at high risk for anxiety and cannabis dependence - completed an online survey including a self-report measure of THC and CBD levels in participants' typically-used cannabis product. Cannabis potency was calculated as THC:CBD ratio (THC%/CBD%) and as relative THC proportion (THC%/[THC%+CBD%]). Cannabis dependence and anxiety levels were self-reported on the Cannabis Use Disorder Identification Test-Revised (CUDIT-R) and Generalized Anxiety Disorder-7 (GAD-7), respectively. Consistent with prior findings in the general population, cannabis potency was significantly positively correlated with cannabis dependence, p = .002, and anxiety levels, p = .020, but only when assessed via THC proportion and not THC:CBD ratio. Consistent with prior research, women reported significantly higher anxiety levels but also unexpectedly, higher THC:CBD ratios, than men. No significant gender differences were found in the associations of either potency measure with either outcome variable. Results are consistent with recent reports of gender convergence in cannabis use prevalence. Additionally, these results identify relative THC proportion as a superior predictor of adverse cannabis and anxiety outcomes than the THC:CBD ratio in both men and women., Competing Interests: Declaration of Competing Interest We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us. We confirm that we have given due consideration to the protection of intellectual property associated with this work and that there are no impediments to publication, including the timing of publication, with respect to intellectual property. In so doing we confirm that we have followed the regulations of our institutions concerning intellectual property. We further confirm that any aspect of the work covered in this manuscript that has involved human patients has been conducted with the ethical approval of all relevant bodies and that such approvals are acknowledged within the manuscript. We understand that the Corresponding Author (Thomas Snooks) is the sole contact for the Editorial process (including Editorial Manager and direct communications with the office). He is responsible for communicating with the other authors about progress, submissions of revisions and final approval of proofs. We confirm that we have provided a current, correct email address which is accessible by the Corresponding Author., (Copyright © 2025 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: Posttraumatic stress disorder (PTSD) and cannabis use disorder (CUD) commonly co-occur. Conditioned associations between psychological trauma cues, distress, cannabis use, and desired relief outcomes may contribute to the comorbidity. These conditioned associations can be studied experimentally by manipulating trauma cue exposure in a cue-reactivity paradigm (CRP) and examining effects on affective and cognitive outcomes in participants with and without PTSD. However, traditional CRPs take place in-lab limiting recruitment/power. We aimed to examine the effects of CRP condition (trauma and neutral) and PTSD group (likely PTSD+ and PTSD-) on affective and craving outcomes using a stand-alone online expressive writing CRP., Methods: Participants ( n  = 202; 43.6% male; M age  = 42.94 years, SD  = 14.71) with psychological trauma histories and past-month cannabis use completed a measure of PTSD symptoms (PTSD Checklist-5 for DSM-5 [PCL-5]) and were randomized to complete either a trauma or neutral expressive writing task. Then they completed validated measures of affect (Positive and Negative Affect Schedule-Short Form [PANAS-SF]) and cannabis craving (Marijuana Craving Questionnaire-Short Form [MCQ-SF])., Results: Linear mixed models tested the hypothesized main and interactive effects of CRP condition (trauma and neutral) and PTSD group (likely PTSD+ and PTSD-) on negative and positive affect (PANAS-SF) and cannabis craving dimensions (MCQ-SF). The hypothesized main effects of trauma versus neutral expressive writing were found for negative affect and the expectancy dimension of cannabis craving and of PTSD group for negative affect and all cannabis craving dimensions; no interactions were observed., Conclusions: Expressive writing appears a useful online CRP. Interventions focused on reducing negative affect and expectancy craving to trauma cues may prevent/treat CUD among cannabis users with PTSD., Plain Language Summary Title: The Use of an Online Expressive Writing as a Trauma Cue Exposure: Effects on Craving and Emotions., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

People with trauma histories have an increased odds of cannabis use. Little is known about the frequency or consequences of different cannabis use regimens in cannabis users with trauma histories. Individuals with anxiety disorders tend to administer benzodiazepines in a pro re nata (PRN; i.e., as needed) as opposed to regularly scheduled (RS, e.g., twice daily [BID], three times daily [TID]) manner. Although physicians tend to prescribe benzodiazepines on a PRN regimen to minimize use, this regimen is paradoxically associated with greater use levels. Indeed, PRN administration regimens may increase use via negative reinforcement processes. We extended this older benzodiazepine literature to cannabis by examining regimen of cannabis use among 94 trauma-exposed cannabis users (mean age = 35.1 years; 52.1 % male; 23.4 % with cannabis prescription). Participants reported their initial and current cannabis use regimen (PRN vs. RS vs. both ['PRN+']) and their past month cannabis use frequency (use occasions in last month) and quantity (grams/use occasion). Consistent with patterns in benzodiazepine research, PRN (47.1 % of sample) and PRN+ (43.5 % of sample) were more common than RS regimens (9.4 % of sample). Also consistent with patterns seen with benzodiazepines, our sample moved toward PRN regimens from initial to current use: e.g., 100 % of initial RS users switched to a regimen that included PRN use. Consistent with predictions emerging from learning theory, PRN and PRN+ cannabis users reported significantly higher cannabis use frequencies compared to RS users (p's < 0.01). Unexpectedly, there were no significant differences between cannabis use regimen groups for quantity of cannabis/occasion. While limited by their cross-sectional nature, with longitudinal replication, result may have implications for identifying cannabis use regimens that minimize frequency of use and thereby reduce risk for negative health outcomes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: While sexual assault may have particularly adverse emotional effects compared with other forms of trauma, it remains unclear which emotional outcome dimensions are impacted, whether cannabis outcomes are similarly impacted, and whether gender differences exist in sexual assault's links with these outcomes., Methods: N  = 100 cannabis users with trauma histories ( M age = 33.1) completed standardized measures of demographics, trauma exposure, posttraumatic stress (PTS) and depressive symptoms, hopelessness, and cannabis outcomes (frequency, medicinal prescription, motives, and craving)., Results: Sexual assault was experienced more often by women (83.9%) than men (31.8%). A series of 2 × 2 analyses of variance [gender: women ( n  = 56) vs. men ( n  = 44) × trauma type: sexual assault ( n  = 61) vs. other ( n  = 39)] and logistic regression revealed that sexual assault survivors scored higher than other trauma survivors on re-experiencing and hyperarousal PTS symptoms (DSM-5 Clusters B and E), cognitive depressive symptoms, hopelessness, cannabis use frequency, medicinal cannabis prescription, cannabis use to cope with psychological symptoms, and compulsivity craving; and lower on social and enhancement cannabis use motives. In terms of gender main effects, women scored higher than men on cannabis use to cope with negative emotions. In terms of interactions for PTS Cluster D symptoms (negative alterations in mood/cognitions), among men only, sexual assault survivors scored higher than other trauma survivors; and for cannabis enhancement motives and purposefulness cannabis craving, among sexual assault survivors only, women scored higher than men., Discussion: Across many different trauma, women survivors' use of cannabis to cope with negative affect should be a specific therapeutic focus. Moreover, we identified specific emotional and cannabis use outcomes that should be of specific clinical concern among sexual assault survivors regardless of gender. Finally, in terms of gender differences of clinical interest among sexual assault survivors, while PTS Cluster D symptoms should be specific treatment targets in men, cannabis enhancement motives and purposefulness craving should be treatment targets in women., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Stewart, Khoury, Watt, Collins, DeGrace and Romero-Sanchiz.)

Trauma cue-elicited activation of automatic cannabis-related cognitive biases are theorized to contribute to comorbid posttraumatic stress disorder and cannabis use disorder. This phenomenon can be studied experimentally by combining the trauma cue reactivity paradigm (CRP) with cannabis-related cognitive processing tasks. In this study, we used a computerized cannabis approach-avoidance task (AAT) to assess automatic cannabis (vs. neutral) approach bias following personalized trauma (vs. neutral) CRP exposure. We hypothesized that selective cannabis (vs. neutral) approach biases on the AAT would be larger among participants with higher PTSD symptom severity, particularly following trauma (vs. neutral) cue exposure. We used a within-subjects experimental design with a continuous between-subjects moderator (PTSD symptom severity). Participants were exposed to both a trauma and neutral CRP in random order, completing a cannabis AAT (cannabis vs. neutral stimuli) following each cue exposure. Current cannabis users with histories of psychological trauma (n = 50; 34% male; mean age = 37.8 years) described their most traumatic lifetime event, and a similarly-detailed neutral event, according to an established interview protocol that served as the CRP. As hypothesized, an AAT stimulus type x PTSD symptom severity interaction emerged (p = .042) with approach bias greater to cannabis than neutral stimuli for participants with higher (p = .006), but not lower (p = .36), PTSD symptom severity. Contrasting expectations, the stimulus type x PTSD symptoms effect was not intensified by trauma cue exposure (p = .19). Selective cannabis approach bias may be chronically activated in cannabis users with higher PTSD symptom severity and may serve as an automatic cognitive mechanism to help explain PTSD-CUD co-morbidity., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: Derived from classical conditioning theory and rooted in motivational mechanisms, cue reactivity paradigms (CRPs) are used in addictions research to measure participants' propensities for substance-relevant responses (e.g., craving) during exposure to substance-relevant cues (e.g., drug paraphernalia). CRPs are also useful in PTSD-addiction comorbidity research, allowing the study of affective and substance-relevant responses to trauma cues. However, studies using traditional CRPs are time-consuming with high attrition rates due to repeat testing. Thus, we sought to test whether a single session semi-structured trauma interview could serve as a CRP in terms of eliciting theorized cue exposure effects on craving and affect measures., Method: Fifty regular cannabis users with trauma histories provided detailed descriptions of their most traumatic lifetime experience, and a neutral experience, according to an established interview protocol. Linear mixed models examined the effect of cue type (trauma vs. neutral) on affective and craving responses., Results: As hypothesized, the trauma interview elicited significantly greater cannabis craving (and alcohol craving among the drinkers), and, greater negative affect among those with more severe PTSD symptoms, compared to the neutral interview., Conclusion: Results suggest an established semi-structured interview may function effectively as a CRP for use in trauma and addictions research., (© 2023 The Authors. International Journal of Methods in Psychiatric Research published by John Wiley & Sons Ltd.)

Conditioned craving to trauma cues and avoidance learning have both been implicated in the high concurrence of trauma-related distress and substance misuse. Using a cue-exposure paradigm involving personalized trauma, cannabis, and neutral cues, we examined if conditioned craving and/or elevated negative affect to trauma cues are mechanisms linking PTSD and cannabis use disorder. Fifty-one trauma-exposed cannabis users were randomly presented the three cue types. Craving and emotional responses were evaluated after each cue using the Marijuana Craving Questionnaire-Short Form (Heishman et al., 2001) and the Positive and Negative Affect Schedule (Watson et al., 1988). Relief cannabis craving (compulsivity and emotionality) was significantly higher after trauma than cannabis and neutral cues (p's < 0.001) and was also higher among those with more severe PTSD symptoms (p's < 0.05). The relationship between PTSD symptom severity and cannabis craving was stronger after trauma than cannabis cues for the compulsivity component of craving (p < .05). Relief craving was also higher after the cannabis cue than after the neutral cue (expectancy and purposefulness; p < .001). Negative affect was significantly higher: after trauma than cannabis and neutral cues (p's < 0.001); and among those with more severe PTSD symptoms (p < . 005). Positive affect was significantly lower after trauma than cannabis cues (p < .05). Trauma cue exposure might promote cannabis misuse through conditioned craving as well as the desire to relieve negative affect. Conditioned cannabis craving involving an uncontrollable compulsion to use cannabis in response to trauma reminders appears particularly likely among cannabis users with more severe PTSD symptoms., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Cannabis use is common among individuals with posttraumatic stress disorder (PTSD), although its use can ultimately worsen PTSD outcomes. Cannabis-use coping motives may help explain the PTSD-cannabis relationship. Frequent pairing of trauma cues with substance use to cope with negative affect can lead to conditioned substance craving. For the present cue-reactivity study, we examined if PTSD symptoms were associated with cannabis craving elicited by a personalized trauma cue and explored whether coping motives mediated this hypothesized relationship; enhancement motives were included as a comparison mediator. Participants (N = 51) were trauma-exposed cannabis users who completed validated assessments on PTSD symptom severity and cannabis use motives. They were then exposed to a personalized audiovisual cue based on their own traumatic experience after which they responded to questions on a standardized measure regarding their cannabis craving. The results demonstrated that PTSD symptoms were associated with increased cannabis craving following trauma cue exposure, B = 0.43, p = .004, 95% CI [0.14, 0.72]. However, the results did not support our hypothesis of an indirect effect through general coping motives, indirect effect = .03, SE = .08, 95% CI [-.10, .21]. We found an independent main effect of general coping motives on trauma cue-elicited cannabis craving, B = 1.86, p = .002, 95% CI [0.72, 3.01]. These findings have important clinical implications suggesting that clinicians should target both PTSD symptoms and general coping motives to prevent the development of conditioned cannabis craving to trauma reminders in trauma-exposed cannabis users., (© 2021 International Society for Traumatic Stress Studies.)

Listening to music aids regulation of emotional arousal and valence (positive vs. negative). Anxiety sensitivity (AS; fear of arousal-related sensations) increases the risk for emotion dysregulation and associated coping behaviors such as substance use and exercise avoidance. The relationship between AS and music listening, however, has received very little attention. This study (1) used exploratory factor analysis of 53 items drawn from three previously validated measures of reasons for music listening to identify the core reasons for listening to music among university students and (2) explored associations between AS and reasons for music listening. Undergraduates (N = 788; 77.7% women; Mage = 19.20, SDage = 2.46) completed the Anxiety Sensitivity Index-3, Motives for Listening to Music Questionnaire, Barcelona Musical Reward Questionnaire, and Brief Music in Mood Regulation Scale. Six core reasons for music listening were identified: Coping, Conformity, Revitalization, Social Enhancement, Connection, and Sensory-Motor. Over and above age and gender, AS was associated with Coping and Conformity-reasons that involve relief from aversive emotions. AS also was associated with listening for Connection reasons. AS was not associated with Revitalization, Social Enhancement, or Sensory-Motor-reasons that involve rewards such as heightened positive emotions. Results suggest that individual differences may influence why people incorporate music listening into their day-to-day lives. Further longitudinal and experimental research is needed to establish directionality and causality in the observed relationship of AS to relief-oriented reasons for music listening. Findings may guide music therapists' efforts to tailor treatment for individuals at risk for anxiety and related mental health problems., (© The Author(s) 2021. Published by Oxford University Press on behalf of American Music Therapy Association. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Granulocyte colony-stimulating factor (G-CSF) has raised much interest because of its role in cocaine addiction in preclinical models. We explored the plasma concentrations of G-CSF in patients diagnosed with substance use disorder (SUD) and highly comorbid psychiatric disorders. In particular, we investigated the association between G-CSF concentrations and comorbid major depressive disorder (MDD) in patients with cocaine and alcohol use disorders (CUD and AUD, respectively). Additionally, patients with MDD but not SUD were included in the study. Three hundred and eleven participants were enrolled in this exploratory study: 136 control subjects, 125 patients with SUD (SUD group) from outpatient treatment programs for cocaine (N = 60, cocaine subgroup) and alcohol (N = 65, alcohol subgroup), and 50 patients with MDD but not SUD (MDD group) from primary-care settings. Participants were assessed based on DSM-IV-TR criteria, and a blood sample was collected to examine the plasma concentrations of G-CSF. G-CSF concentrations were negatively correlated with age in the entire sample (r = - 0.233, p < 0.001) but not in the patients with MDD. G-CSF concentrations were lower in patients with SUD than in controls (p < 0.05), specifically in the cocaine subgroup (p < 0.05). Patients with SUD and comorbid MDD had lower G-CSF concentrations than patients with SUD but not comorbid MDD or controls (p < 0.05). In contrast, patients with MDD but not SUD showed no differences compared with their controls. The negative association between G-CSF concentrations and age in the sample was not observed in patients with MDD. G-CSF concentrations were decreased in patients with SUD and comorbid MDD but not in patients with MDD. Therefore, G-CSF may be useful to improve the stratification of patients with dual diagnosis seeking treatment. Further investigation is needed to explore the impact of sex and type of drug on the expression of G-CSF.

Objective: Female post-secondary students typically engage in less physical activity than their male counterparts. Given that women have greater anxiety sensitivity (ie, fear of arousal-based body sensations) and anxiety sensitivity is inversely related to physical activity participation, this study sought to determine if anxiety sensitivity mediates gender differences in self-reported physical activity. Participants and methods : A sample of 802 post-secondary students completed the Anxiety Sensitivity Index-3 and a Lifestyles Questionnaire in September 2017. Results: Women reported significantly less physical activity and significantly greater anxiety sensitivity. Anxiety sensitivity was significantly and inversely related to self-reported physical activity. A significant indirect effect of gender on physical activity via anxiety sensitivity was shown ( B  = 5.56, SE  = 2.81, p  < .05, 95% CI [1.31, 12.78], P M  = .0843). Conclusions: Results suggest that anxiety sensitivity partially explains gender differences in physical activity. Anxiety sensitivity reduction interventions might increase physical activity participation and reduce the existing gender gap.

How the presence of inflammation has repercussions for brain function is a topic of active research into depression. Signals released from immune system-related cells, including chemokines, might be indicative of active depression and can, hypothetically, serve as biomarkers of response to interventions, both pharmacological and psychological. The objective of this study is to analyze the peripheral plasma concentrations of CXCL12, CCL11, CX3CL1 and CCL2 in a cohort of depressed primary-care patients, as well as their evolution after an internet-based cognitive-behavioral intervention. The concentrations of those chemokines were measured in 66 primary-care patients with mild and moderate depression, before and after the intervention, as well as 60 controls, using multiplex immunoassays. Concentrations of CXCL12 and CCL2 were significantly higher in the clinical sample in comparison with controls. A stable multivariate discriminative model between both groups was found. Concentrations of all chemokines decreased after the internet-based psychological intervention. These findings support the implication of chemokines in depression, even in a sample of patients with mild and moderate severity. Furthermore, they demonstrate the need for further multidisciplinary research that confirms how biomarkers such as plasma chemokines can serve as a marker for depression and are sensitive to non-pharmacological interventions.

Purpose: Achondroplasia, as the most common form of disproportionate short stature, potentially impacts the health-related quality of life (HRQOL) and functioning of people with this condition. Because there are no psychometrically validated patient-reported outcome (PRO) condition-specific instruments for achondroplasia, this study selected and tested available generic, disease-specific and under development questionnaires for possible use in multinational clinical research., Methods: A three-step approach was applied. First, a literature review and clinician/expert opinions were used to select relevant PRO questionnaires. Second, focus group discussions, including a group cognitive debriefing for piloting of the questionnaires with children/adolescents with achondroplasia and their parents, were performed in Spain and Germany. Third, a field-test study was conducted to test the psychometric properties of these instruments., Results: Six questionnaires were identified as potentially relevant in children with achondroplasia. In each country, five focus groups including a cognitive debriefing were conducted, and the results narrowed the possibilities to three instruments as most appropriate to assess HRQOL (the generic PedsQL, the height-specific QoLISSY, and the achondroplasia-specific APLES). Results of the field study indicate the QoLISSY and the PedsQL questionnaires to be most appropriate for use in clinical research at this time., Conclusion: This selection study is a step forward in assessing the impact of achondroplasia on HRQOL. Of the instruments examined, the QoLISSY and the PedsQL both capture items relevant to children with achondroplasia and have met the psychometric validation criteria needed for use in research. The APLES instrument is a promising tool that should be revisited upon psychometric validation.

Rationale: the role that antidepressants play on alcohol consumption is not well understood. Previous studies have reported that treatment with a Selective Serotonin Reuptake Inhibitor (SSRIs) increases alcohol consumption in an animal model of relapse, however it is unknown whether this effect holds for other antidepressants such as the atypical dopamine/norepinephrine reuptake inhibitors (SNDRI)., Objectives: the main goal of the present study was to compare the effects of two classes of antidepressants drugs, bupropion (SNDRI) and fluoxetine (SSRI), on alcohol consumption during relapse. Since glutamatergic and endocannabinoid signaling systems plays an important role in alcohol abuse and relapse, we also evaluated the effects of both antidepressants onthe expression of the main important genes and proteins of both systems in the prefrontal cortex, a critical brain region in alcohol relapse., Methods: rats were trained to self-administered alcohol. During abstinence, rats received a 14d-treatment with vehicle, fluoxetine (10 mg/kg) or bupropion (20 mg/kg), and we evaluated alcohol consumption during relapse for 3 weeks. Samples of prefrontal cortex were taken to evaluate the mRNA and protein expression of the different components of glutamatergic and endocannabinoid signaling systems., Results: fluoxetine treatment induced a long-lasting increase in alcohol consumption during relapse, an effect that was not observed in the case of bupropion treatment. The observed increases in alcohol consumption were accompanied by distinct alterations in the glutamate and endocannabinoid systems., Conclusions: our results suggest that SSRIs can negatively impact alcohol consumption in relapse while SNDRIs have no effects. The observed increase in alcohol consumption are accompanied by functional alterations in the glutamatergic and endocannabinoid systems. This finding could open new strategies for the treatment of depression in patients with alcohol use disorders., (Copyright © 2019. Published by Elsevier B.V.)

Oleoylethanolamide (OEA) is a non-cannabinoid acylethanolamide with multiple physiological roles that has been proposed to have antidepressant-like activity in preclinical models. OEA shares biosynthetic pathways with anandamide (AEA) a transmitter involved in affective disorders and anxiety in humans. However, although the participation of OEA in depression has been proposed, both, the contribution of OEA to the depressive phenotype and the effect of antidepressant therapy on circulating levels of this and related non-cannabinoid acylethanolamides in humans are basically unknown. The main objective of this study is to compare the plasma concentrations of OEA and related acylethanolamides in a sample of primary care patients with depression (n = 69) with those of healthy non-depressed patients (n = 47). At the time of admission to the study, 22 patients were under selective serotonin reuptake inhibitor (SSRI) antidepressant treatment and 47 patients were not receiving any type of intervention. In addition, plasma concentrations of the endocannabinoid 2-AG and two related monoacylglycerols were monitored. Plasma OEA concentrations were found to be elevated in depressed patients and to correlate with somatic symptoms of depression. Plasma concentrations of both, AEA and 2-AG, were found to be elevated also in depressed patients. Further analysis demonstrated that the elevation observed in the plasma concentrations of both, OEA and 2-AG, was associated to SSRI antidepressant therapy at the time of recruitment. Further clinical research is needed to understand whether SSRI-induced elevations in OEA levels contribute to the response to SSRI in depressed patients as described in preclinical models., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Introduction: Here, we present the first description of the Andalusian Bipolar Family (ABiF) Study. This longitudinal investigation of families from Andalusia, Spain commenced in 1997 with the aim of elucidating the molecular genetic causes of bipolar affective disorder. The cohort has since contributed to a number of key genetic findings, as reported in international journals. However, insight into the genetic underpinnings of the disorder in these families remains limited., Method: In the initial 1997-2003 study phase, 100 multiplex bipolar disorder and other mood disorder families were recruited. The ongoing second phase of the project commenced in 2013, and involves follow-up of a subgroup of the originally recruited families. The aim of the follow-up investigation is to generate: i) longitudinal clinical data; ii) results from detailed neuropsychological assessments; and iii) a more extensive collection of biomaterials for future molecular biological studies., Results: The ABiF Study will thus generate a valuable resource for future investigations into the aetiology of bipolar affective disorder; in particular the causes of high disease loading within multiply affected families., Discussion: We discuss the value of this approach in terms of new technologies for the identification of high-penetrance genetic factors. These new technologies include exome and whole genome sequencing, and the use of induced pluripotent stem cells or model organisms to determine functional consequences., (Copyright © 2017 SEP y SEPB. Publicado por Elsevier España, S.L.U. All rights reserved.)

The identification of growth factors as potential biomarkers in alcohol addiction may help to understand underlying mechanisms associated with the pathogenesis of alcohol use disorders (AUDs). Previous studies have linked growth factors to neural plasticity in neurocognitive impairment and mental disorders. In order to further clarify the impact of chronic alcohol consumption on circulating growth factors, a cross-sectional study was performed in abstinent AUD patients (alcohol group, N = 91) and healthy control subjects (control group, N = 55) to examine plasma concentrations of brain-derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1) and IGF-1 binding protein-3 (IGFBP-3). The association of these plasma peptides with relevant AUD-related variables and psychiatric comorbidity was explored. The alcohol group was diagnosed with severe AUD and showed an average of 13 years of problematic use and 10 months of abstinence at the moment of participating in the study. Regarding common medical conditions associated with AUD, we observed an elevated incidence of alcohol-induced liver and pancreas diseases (18.7%) and psychiatric comorbidity (76.9%). Thus, AUD patients displayed a high prevalence of dual diagnosis (39.3%) [mainly depression (19.9%)] and comorbid substance use disorders (40.7%). Plasma BDNF and IGF-1 concentrations were significantly lower in the alcohol group than in the control group (p<0.001). Remarkably, there was a negative association between IGF-1 concentrations and age in the control group (r = -0.52, p<0.001) that was not found in the alcohol group. Concerning AUD-related variables, AUD patients with liver and pancreas diseases showed even lower concentrations of BDNF (p<0.05). In contrast, the changes in plasma concentrations of these peptides were not associated with abstinence, problematic use, AUD severity or lifetime psychiatric comorbidity. These results suggest that further research is necessary to elucidate the role of BDNF in alcohol-induced toxicity and the biological significance of the lack of correlation between age and plasma IGF-1 levels in abstinent AUD patients.

Differences and similarities between intrusive thoughts typical of obsessive-compulsive disorder, generalized anxiety disorder, and hypochondriasis are relevant for their differential diagnosis, formulation, and psychological treatment. Previous research in non-clinical samples pointed out the relevance of some process variables, such as responsibility, guilt, or neutralization strategies. This research is aimed to investigate the differences and similarities between clinical obsessions, worries, and illness intrusions in some of these process variables. A second aim is to identify models based on these variables that could reliably differentiate between them. Three groups of patients with obsessive-compulsive disorder (n = 35; 60% women, mean age 38.57), generalized anxiety disorder (n = 36; 61.1% women, mean age 41.50), and hypochondriasis (n = 34; 70.6% women, mean age 31.59) were evaluated using the Cognitive Intrusions Questionnaire-Transdiagnostic Version (Romero-Sanchiz, Nogueira-Arjona, Godoy-Ávila, Gavino-Lázaro, & Freeston, ). The results showed that some appraisals (e.g., responsibility or egodystonicity), emotions (e.g., guilt or insecurity), neutralization strategies, and other variables (e.g., verbal content or trigger from body sensation) are relevant for the discrimination between obsessions, worries, and illness intrusions. The results also showed 3 stable models based on these variables for the discrimination between these thoughts. The implication of these results in the diagnosis, formulation, and psychological treatment of obsessive-compulsive disorder, generalized anxiety disorder, and hypochondriasis is discussed., (Copyright © 2017 John Wiley & Sons, Ltd.)

Background: Cocaine use disorder (CUD) is a complex health condition, especially when it is accompanied by comorbid psychiatric disorders (dual diagnosis). Dual diagnosis is associated with difficulties in the stratification and treatment of patients. One of the major challenges in clinical practice of addiction psychiatry is the lack of objective biological markers that indicate the degree of consumption, severity of addiction, level of toxicity and response to treatment in patients with CUD. These potential biomarkers would be fundamental players in the diagnosis, stratification, prognosis and therapeutic orientation in addiction. Due to growing evidence of the involvement of the immune system in addiction and psychiatric disorders, we tested the hypothesis that patients with CUD in abstinence might have altered circulating levels of signaling proteins related to systemic inflammation., Methods: The study was designed as a cross-sectional study of CUD treatment-seeking patients. These patients were recruited from outpatient programs in the province of Malaga (Spain). The study was performed with a total of 160 white Caucasian subjects, who were divided into the following groups: patients diagnosed with CUD in abstinence ( N  = 79, cocaine group) and matched control subjects ( N  = 81, control group). Participants were clinically evaluated with the diagnostic interview PRISM according to the DSM-IV-TR, and blood samples were collected for the determination of chemokine C-C motif ligand 11 (CCL11, eotaxin-1), interferon gamma (IFNγ), interleukin-4 (IL-4), interleukin-8 (IL-8), interleukin-17α (IL-17α), macrophage inflammatory protein 1α (MIP-1α) and transforming growth factor α (TGFα) levels in the plasma. Clinical and biochemical data were analyzed in order to find relationships between variables., Results: While 57% of patients with CUD were diagnosed with dual diagnosis, approximately 73% of patients had other substance use disorders. Cocaine patients displayed greater cocaine symptom severity when they were diagnosed with psychiatric comorbidity. Regarding inflammatory factors, we observed significantly lower plasma levels of IL-17α ( p  < 0.001), MIP-1α ( p  < 0.001) and TGFα ( p  < 0.05) in the cocaine group compared with the levels in the control group. Finally, there was a significant primary effect of dual diagnosis on the plasma concentrations of TGFα ( p  < 0.05) in the cocaine group, and these levels were lower in patients with dual diagnoses., Discussion: IL-17α, MIP-1α and TGFα levels are different between the cocaine and control groups, and TGFα levels facilitate the identification of patients with dual diagnosis. Because TGFα reduction is associated with enhanced responses to cocaine in preclinical models, we propose TGFα as a potential biomarker of complex CUD in humans., Competing Interests: The authors declare there are no competing interests.

Cocaine continues to be a worldwide public health concern in Europe. To improve prognosis and intervention, it is necessary to understand the characteristics of the patients who depend on the services where they receive care. The objective is to analyze the differences among patients who use cocaine and between ambulatory and residential resources to better adapt treatment. This is a descriptive, observational study of two populations of cocaine users in treatment: the ambulatory therapeutic community (ATC) and the therapeutic community (TC). The PRISM diagnostic interview was used for both groups. An analysis of both populations indicates a high prevalence of cocaine, heroin, cannabis, sedative, psychostimulant, and hallucinogen use disorders in the TC population compared to the ATC. In alcohol use disorder, differences between both mental health services were not observed. The degree of severity of cocaine use disorders (CUD) is greater in the TC population. The prevalence of psychiatric comorbidity is not statistically significant between the two populations, except for primary psychotic disorders, which are more prevalent in the TC population. This difference in the prevalence of psychotic disorders may be related to the high prevalence of cannabis use disorders in TC patients. Differences in the prevalence of substance use disorders, severity of CUD, and psychiatric comorbidity may limit the efficiency of mental health services involved in substance use disorder therapeutics. These results suggest the need for careful and extensive phenotyping of patients to improve intervention and prognosis in a clinical resource-dependent manner.

Acylethanolamides are a family of endogenous lipid mediators that are involved in physiological and behavioral processes associated with addiction. Recently, oleoylethanolamide (OEA) has been reported to reduce alcohol intake and relapse in rodents but the contribution of OEA and other acylethanolamides in alcohol addiction in humans is unknown. The present study is aimed to characterize the plasma acylethanolamides in alcohol dependence. Seventy-nine abstinent alcohol-dependent subjects (27 women) recruited from outpatient treatment programs and age-/sex-/body mass-matched healthy volunteers (28 women) were clinically assessed with the diagnostic interview PRISM according to the DSM-IV-TR after blood extraction for quantification of acylethanolamide concentrations in the plasma. Our results indicate that all acylethanolamides were significantly increased in alcohol-dependent patients compared with control subjects (p < 0.001). A logistic model based on these acylethanolamides was developed to distinguish alcohol-dependent patients from controls and included OEA, arachidonoylethanolamide (AEA) and docosatetraenoylethanolamide (DEA), providing a high discriminatory power according to area under the curve [AUC = 0.92 (95%CI: 0.87-0.96), p < 0.001]. Additionally, we found a significant effect of the duration of alcohol abstinence on the concentrations of OEA, AEA and DEA using a regression model (p < 0.05, p < 0.01 and p < 0.001, respectively), which was confirmed by a negative correlation (rho = -0.31, -0.40 and -0.44, respectively). However, acylethanolamides were not influenced by the addiction alcohol severity, duration of problematic alcohol use or diagnosis of psychiatric comorbidity. Our results support the preclinical studies and suggest that OEA, AEA and DEA are altered in alcohol-dependence during abstinence and that might act as potential markers for predicting length of alcohol abstinence., (© 2016 Society for the Study of Addiction.)

Depression is one of the most common mental disorders and will become one of the leading causes of disability in the world. Internet-based CBT programs for depression have been classified as "well established" following the American Psychological Association criteria for empirically supported treatments. The aim of this study is to analyze the cost effectiveness at 12-month follow-up of the Internet-based CBT program "Smiling is fun" with (LITG) and without psychotherapist support (TSG) compared to usual care. The perspective used in our analysis is societal. A sample of 296 depressed patients (mean age of 43.04 years; 76% female; BDI-II mean score = 22.37) from primary care services in four Spanish regions were randomized in the RCT. The complete case and intention-to-treat (ITT) perspectives were used for the analyses. The results demonstrated that both Internet-based CBT interventions exhibited cost utility and cost effectiveness compared with a control group. The complete case analyses revealed an incremental cost-effectiveness ratio (ICER) of €-169.50 and an incremental cost-utility ratio (ICUR) of €-11389.66 for the TSG group and an ICER of €-104.63 and an ICUR of €-6380.86 for the LITG group. The ITT analyses found an ICER of €-98.37 and an ICUR of €-5160.40 for the TSG group and an ICER of €-9.91 and an ICUR of €496.72 for the LITG group. In summary, the results of this study indicate that the two Internet-based CBT interventions are appropriate from both economic and clinical perspectives for depressed patients in the Spanish primary care system. These interventions not only help patients to improve clinically but also generate societal savings., Trial Registration: clinicaltrials.gov NCT01611818.

Recent studies have linked changes in peripheral chemokine concentrations to the presence of both addictive behaviors and psychiatric disorders. The present study further explore this link by analyzing the potential association of psychiatry comorbidity with alterations in the concentrations of circulating plasma chemokine in patients of both sexes diagnosed with alcohol use disorders (AUD). To this end, 85 abstinent subjects with AUD from an outpatient setting and 55 healthy subjects were evaluated for substance and mental disorders. Plasma samples were obtained to quantify chemokine concentrations [C-C motif (CC), C-X-C motif (CXC), and C-X 3 -C motif (CX 3 C) chemokines]. Abstinent AUD patients displayed a high prevalence of comorbid mental disorders (72%) and other substance use disorders (45%). Plasma concentrations of chemokines CXCL12/stromal cell-derived factor-1 ( p  < 0.001) and CX 3 CL1/fractalkine ( p  < 0.05) were lower in AUD patients compared to controls, whereas CCL11/eotaxin-1 concentrations were strongly decreased in female AUD patients ( p  < 0.001). In the alcohol group, CXCL8 concentrations were increased in patients with liver and pancreas diseases and there was a significant correlation to aspartate transaminase ( r  = +0.456, p  < 0.001) and gamma-glutamyltransferase ( r  = +0.647, p  < 0.001). Focusing on comorbid psychiatric disorders, we distinguish between patients with additional mental disorders ( N  = 61) and other substance use disorders ( N  = 38). Only CCL11 concentrations were found to be altered in AUD patients diagnosed with mental disorders ( p  < 0.01) with a strong main effect of sex. Thus, patients with mood disorders ( N  = 42) and/or anxiety ( N  = 16) had lower CCL11 concentrations than non-comorbid patients being more evident in women. The alcohol-induced alterations in circulating chemokines were also explored in preclinical models of alcohol use with male Wistar rats. Rats exposed to repeated ethanol (3 g/kg, gavage) had lower CXCL12 ( p  < 0.01) concentrations and higher CCL11 concentrations ( p  < 0.001) relative to vehicle-treated rats. Additionally, the increased CCL11 concentrations in rats exposed to ethanol were enhanced by the prior exposure to restraint stress ( p  < 0.01). Concordantly, acute ethanol exposure induced changes in CXCL12, CX 3 CL1, and CCL11 in the same direction to repeated exposure. These results clearly indicate a contribution of specific chemokines to the phenotype of AUD and a strong effect of sex, revealing a link of CCL11 to alcohol and anxiety/stress.

Alcohol addiction is associated with high psychiatric comorbidity. Objective stratification of patients is necessary to optimize care and improve prognosis. The present study is designed to gain insights into this challenge by addressing the following objectives: a) to estimate the prevalence of psychiatric comorbidities in a sample of outpatients seeking treatment for alcohol use disorder, b) to describe the existence of gender differences and c) to validate 2-acyl-glycerols as biomarkers of alcohol use disorder and/or psychiatric comorbidity. One hundred and sixty-two patients were recruited and evaluated with the semi-structured interview PRISM. The presence of psychopathology was associated with a greater number of criteria for alcohol abuse and dependence according to DSM-IV-TR. We found gender differences in psychiatric comorbidity, e.g., mood disorder, as well as in comorbid substance use disorders. The prevalence of lifetime psychiatric comorbidity was 68.5%, with mood disorders the most frequent (37%), followed by attention deficit disorder (24.7%) and anxiety disorders (17.9%). Substance-induced disorders were more frequent in mood and psychotic disorders, whereas the primary disorders were more prevalent in patients with comorbid anxiety disorders. We found that 2-acyl-glycerols were significantly decreased in comorbid anxiety disorders in alcohol dependent patients in the last year, which makes them a potential biomarker for this psychopathological condition.

Background: Depression is the most prevalent cause of illness-induced disability worldwide. Face-to-face psychotherapeutic interventions for depression can be challenging, so there is a need for other alternatives that allow these interventions to be offered. One feasible alternative is Internet-based psychological interventions. This is the first randomized controlled trial (RCT) on the effectiveness of an Internet-based intervention on depression in primary health care in Spain., Objective: Our aim was to compare the effectiveness of a low-intensity therapist-guided (LITG) Internet-based program and a completely self-guided (CSG) Internet-based program with improved treatment as usual (iTAU) care for depression., Methods: Multicenter, three-arm, parallel, RCT design, carried out between November 2012 and January 2014, with a follow-up of 15 months. In total, 296 adults from primary care settings in four Spanish regions, with mild or moderate major depression, were randomized to LITG (n=96), CSG (n=98), or iTAU (n=102). Research completers at follow-up were 63.5%. The intervention was Smiling is Fun, an Internet program based on cognitive behavioral therapy. All patients received iTAU by their general practitioners. Moreover, LITG received Smiling is Fun and the possibility of psychotherapeutic support on request by email, whereas CSG received only Smiling is Fun. The main outcome was the Beck Depression Inventory-II at 3 months from baseline. Mixed-effects multilevel analysis for repeated measures were undertaken., Results: There was no benefit for either CSG [(B coefficient=-1.15; P=.444)] or LITG [(B=-0.71; P=.634)] compared to iTAU, at 3 months. There were differences at 6 months [iTAU vs CSG (B=-4.22; P=.007); iTAU vs LITG (B=-4.34; P=.005)] and 15 months [iTAU vs CSG (B=-5.10; P=.001); iTAU vs LITG (B=-4.62; P=.002)]. There were no differences between CSG and LITG at any time. Adjusted and intention-to-treat models confirmed these findings., Conclusions: An Internet-based intervention for depression combined with iTAU conferred a benefit over iTAU alone in the Spanish primary health care system., Trial Registration: Clinicaltrials.gov NCT01611818; https://register.clinicaltrials.gov/prs/app/action/SelectProtocol? selectaction=Edit&uid=U0001NPQ&ts=2&cx=gctdh2&sid=S0003KJ6 (Archived by WebCite at http://www.webcitation.org/6jbsUvUDz)., Competing Interests: Conflicts of Interest: None declared.

Background: One-quarter of the world's population will suffer from depression symptoms at some point in their lives. Mental health services in developed countries are overburdened. Therefore, cost-effective interventions that provide mental health care solutions such as Web-based psychotherapy programs have been proposed., Objective: The intent of the study was to identify expectations regarding Web-based psychotherapy for the treatment of depression in primary care among patients and health professionals that might facilitate or hinder its effects., Methods: The expectations of untreated patients and health professionals were examined by means of interviews and focus groups. There were 43 participants (20 patients with mild and moderate levels of depression, 11 primary care physicians, and 12 managers; 22 of them for interviews and 21 for groups). A thematic content analysis from the grounded theory for interviews, and an analysis of the discursive positions of participants based on the sociological model for groups were performed. Interpretations were achieved by agreement between three independent analysts., Results: All participants showed a good general acceptance of Web-based psychotherapy, appreciating possible advantages and improvements. Patients, physicians, and managers shared the same conceptualization of their expectations, although highlighting different aspects. Patients focused on the need for individualized and personalized interaction, while professionals highlighted the need for the standardization of the program. Physicians were concerned with extra workload, while managers were worried about optimizing cost-effectiveness., Conclusions: Expectations of the different participants can conflict with each other. Finding a balanced position among them is needed if we are to harmoniously implement effective Web-based interventions for depression in routine clinical practice.

Recent studies have identified biomarkers related to the severity and pathogenesis of cocaine addiction and common comorbid psychiatric disorders. Monitoring these plasma mediators may improve the stratification of cocaine users seeking treatment. Because the neurotrophic factors are involved in neural plasticity, neurogenesis and neuronal survival, we have determined plasma concentrations of brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 (IGF-1) and IGF-1 binding protein 3 (IGFBP-3) in a cross-sectional study with abstinent cocaine users who sought outpatient treatment for cocaine (n = 100) and age/body mass matched controls (n = 85). Participants were assessed with the diagnostic interview 'Psychiatric Research Interview for Substance and Mental Disorders'. Plasma concentrations of these peptides were not different in cocaine users and controls. They were not associated with length of abstinence, duration of cocaine use or cocaine symptom severity. The pathological use of cocaine did not influence the association of IGF-1 with age observed in healthy subjects, but the correlation between IGF-1 and IGFBP-3 was not significantly detected. Correlation analyses were performed between these peptides and other molecules sensitive to addiction: BDNF concentrations were not associated with inflammatory mediators, lipid derivatives or IGF-1 in cocaine users, but correlated with chemokines (fractalkine/CX3CL1 and SDF-1/CXCL12) and N-acyl-ethanolamines (N-palmitoyl-, N-oleoyl-, N-arachidonoyl-, N-linoleoyl- and N-dihomo-γ-linolenoyl-ethanolamine) in controls; IGF-1 concentrations only showed association with IGFBP-3 concentrations in controls; and IGFBP-3 was only correlated with N-stearoyl-ethanolamine concentrations in cocaine users. Multiple substance use disorders and life-time comorbid psychopathologies were common in abstinent cocaine users. Interestingly, plasma BDNF concentrations were exclusively found to be decreased in users diagnosed with both primary and cocaine-induced disorders for mood and anxiety disorders. In summary, BDNF, IGF-1 and IGFBP-3 were not affected by a history of pathological use of cocaine supported by the absence of associations with other molecules sensitive to cocaine addiction. However, BDNF was affected by comorbid mood disorders. Further research is necessary to elucidate the role of BDNF and IGF-1 in the transition to cocaine addiction and associated psychiatric comorbidity.

There are sex differences in the progression of drug addiction, relapse, and response to therapies. Because biological factors participate in these differences, they should be considered when using biomarkers for addiction. In the current study, we evaluated the sex differences in psychiatric comorbidity and the concentrations of plasma mediators that have been reported to be affected by cocaine. Fifty-five abstinent cocaine-addicted subjects diagnosed with lifetime cocaine use disorders (40 men and 15 women) and 73 healthy controls (48 men and 25 women) were clinically assessed with the diagnostic interview "Psychiatric Research Interview for Substance and Mental Disorders." Plasma concentrations of chemokines, cytokines, N-acyl-ethanolamines, and 2-acyl-glycerols were analyzed according to history of cocaine addiction and sex, controlling for covariates age and body mass index (BMI). Relationships between these concentrations and variables related to cocaine addiction were also analyzed in addicted subjects. The results showed that the concentrations of chemokine (C-C motif) ligand 2/monocyte chemotactic protein-1 (CCL2/MCP-1) and chemokine (C-X-C motif) ligand 12/stromal cell-derived factor-1 (CXCL12/SDF-1) were only affected by history of cocaine addiction. The plasma concentrations of interleukin 1-beta (IL-1β), IL-6, IL-10, and tumor necrosis factor-alpha (TNFα) were affected by history of cocaine addiction and sex. In fact, whereas cytokine concentrations were higher in control women relative to men, these concentrations were reduced in cocaine-addicted women without changes in addicted men. Regarding fatty acid derivatives, history of cocaine addiction had a main effect on the concentration of each acyl derivative, whereas N-acyl-ethanolamines were increased overall in the cocaine group, 2-acyl-glycerols were decreased. Interestingly, N-palmitoleoyl-ethanolamine (POEA) was only increased in cocaine-addicted women. The covariate BMI had a significant effect on POEA and N-arachidonoyl-ethanolamine concentrations. Regarding psychiatric comorbidity in the cocaine group, women had lower incidence rates of comorbid substance use disorders than did men. For example, alcohol use disorders were found in 80% of men and 40% of women. In contrast, the addicted women had increased prevalences of comorbid psychiatric disorders (i.e., mood, anxiety, and psychosis disorders). Additionally, cocaine-addicted subjects showed a relationship between the concentrations of N-stearoyl-ethanolamine and 2-linoleoyl-glycerol and diagnosis of psychiatric comorbidity. These results demonstrate the existence of a sex influence on plasma biomarkers for cocaine addiction and on the presence of comorbid psychopathologies for clinical purposes.