Beta-Caryophyllene, a Cannabinoid Receptor Type 2 Selective Agonist, in Emotional and Cognitive Disorders.

Mental disorders account for one of the most prevalent categories of the burden of disease worldwide, with depression expected to be the largest contributor by 2030, closely followed by anxiety. The COVID-19 pandemic possibly exacerbated these challenges, especially amongst adolescents, who experienced isolation, disrupted routines, and limited healthcare access. Notably, the pandemic has been associated with long-term neurological effects known as "long-COVID", characterized by both cognitive and psychopathological symptoms. In general, psychiatric disorders, including those related to long-COVID, are supposed to be due to widespread inflammation leading to neuroinflammation. Recently, the endocannabinoid system (ECS) emerged as a potential target for addressing depression and anxiety pathophysiology. Specifically, natural or synthetic cannabinoids, able to selectively interact with cannabinoid type-2 receptor (CB2R), recently revealed new therapeutic potential in neuropsychiatric disorders with limited or absent psychotropic activity. Among the most promising natural CB2R ligands, the bicyclic sesquiterpene ß-caryophyllene (BCP) has emerged as an excellent anti-inflammatory and antioxidant therapeutic agent. This review underscores BCP's immunomodulatory and anti-inflammatory properties, highlighting its therapeutic potential for the management of depression and anxiety.

Factor structure and reliability of the Italian adaptation of the Hypomania Check List-32, second revision (HCL-32-R2).

OBJECTIVE: To assess the psychometric properties of the Italian adaptation of the Hypomania-Check-List 32-item, second revision (HCL-32-R2) for the detection of bipolarity in major depressive disorder (MDD) treatment-seeking outpatients. METHODS: A back-to-back Italian adaption of the "Bipolar Disorders: Improving Diagnosis, Guidance, and Education" English module of the HCL-32-R2 was administered between March 2013 and October 2014 across twelve collaborating sites in Italy. Diagnostic and Statistical Manual Fourth edition (DSM-IV) diagnoses were made adopting the mini-international neuropsychiatric interview, using bipolar disorder (BD) patients as controls. RESULTS: In our sample (n=441, of whom, BD-I=68; BD-II=117; MDD=256), using a cut-off of 14 allowed the HCL-32-R2 to discriminate DSM-IV-defined MDD patients between "true unipolar" (HCL-32-R2(-)) and "sub-threshold bipolar depression" (HCL-32-R2(+)) with sensitivity=89% and specificity=79%. Area under the curve was .888; positive and negative predictive values were 75.34% and 90.99% respectively. Owing to clinical interpretability considerations and consistency with previous adaptations of the HCL-32, a two-factor solution (F1="hyperactive/elated" vs. F2="irritable/distractible/impulsive") was preferred using exploratory and confirmatory factor analyses, whereas items n.33 ("I gamble more") and n.34 ("I eat more") introduced in the R2 version of the scale slightly loaded onto F2 and F1 respectively. Cronbach׳s α=.88 for F1 and .71 for F2. LIMITATIONS: No cross-validation with any additional validated screening tool; treatment-seeking outpatient sample; recall bias; no systematic evaluation of eventual medical/psychiatric comorbidities, current/lifetime pharmacological history, neither record of severity of current MDE. CONCLUSIONS: Our results seem to indicate fair accuracy of HCL-32 as a screening instrument for BD, though replication studies are warranted.

Pathological gambling and impulsivity: an Italian study.

AIM: Although the precise nature of pathological gambling (PG) is still elusive, currently it is considered an impulse-control disorder that shares several features with substance dependence, such as deficit in self-regulation and impaired impulsivity. The aim of this study was to evaluate the impulsivity of PG patients by means of the Barratt Impulsivity Scale, version 11 (BIS-11), as compared with healthy control subjects, and to explore the possible correlations with gambling severity. METHODS: Thirty-five outpatients (all men) with a diagnosis of PG were recruited at their first psychiatric interview in a psychiatric outpatient ward, and compared with a similar group of healthy control subjects. The severity of PG was assessed by means of the South Oaks Gambling Screen (SOGS). RESULTS: The results showed that the BIS-11 total score, as well as the scores of different factors (motor impulsity and cognitive complexity) and subscales (motor and non-planning impulsivity) were significantly higher in PG patients than in control subjects. In addition, positive correlations were detected between the SOGS and the BIS-11 total scores, and the attention and cognitive instability factor scores, or the attentional and motor impulsivity (rs=0.459, p=.021) subscale scores. CONCLUSIONS: These findings support the notion that impulsivity represents a core element of PG linked to the severity of the clinical picture.

The impact of mood, anxiety, and sleep disorders on fibromyalgia.

INTRODUCTION: Several studies carried out mainly in North America revealed high rates of mood, anxiety and sleep disorders in patients with fibromyalgia (FM), while the information in other countries is scant. Therefore, we aimed at investigating the prevalence and the impact of such conditions on the health-related quality of life (HRQoL) and the severity of pain in a sample of Italian FM patients. METHODS: One-hundred and sixty-seven women suffering from primary FM were consecutively enrolled. Psychiatric diagnoses were made by means of DSM-IV criteria. The HRQoL and the severity of pain were measured through the Medical Outcomes Study 36-item Short-Form Health Survey (MOS-SF-36) and the FM Impact Questionnaire (FIQ). RESULTS: Fibromyalgia patients showed a high rate (80.8%) of lifetime and/or current comorbidity with mood and anxiety disorders. Patients with psychiatric comorbidity resulted significantly more impaired on the Mental Component Summary score of the MOS-SF-36 and showed a higher FIQ total score than those suffering from FM only. The severity of pain was associated with current psychiatric comorbidity. Patients with current mood disorders showed significantly lower Mental and Physical Component Summary scores of the MOS-SF-36 and higher FIQ total scores than those with current anxiety disorders or those without psychiatric comorbidity. Finally, patients with sleep disorders reported a lower HRQoL than those with a normal sleep, and specifically those with difficulty in falling in sleep had higher severity of pain. CONCLUSION: Psychiatric comorbidity, in particular with mood disorders, provokes a significant impairment of the HRQoL and, when current, a higher severity of pain in FM patients.

Romantic attachment and subtypes/dimensions of jealousy.

The present study explored the possible relationship between romantic attachment and jealousy in 100 healthy subjects. The romantic attachment and jealousy were evaluated by means of, respectively, the "Experiences in Close Relationships" questionnaire (ECR), and the "Questionario della Gelosia" (QUEGE). The ECR anxiety scale was related to all QUEGE dimensions, while the ECR avoidance scale to three. Individuals with the preoccupied attachment style showed higher scores than secure subjects on the obsessionality, interpersonal sensitivity and fear of loss dimensions. Fearful-avoidant individuals had higher score than secure subjects on the fear of loss dimension only, while dismissing individuals had lower scores on the self-esteem dimension.These findings suggest that romantic attachment and jealousy are intertwined.

Trazodone effects on [H]-paroxetine and alpha(2)-adrenoreceptors in platelets of patients with major depression.

Trazodone is an antidepressant which behaves as a selective 5-HT(2) antagonist and 5-HT reuptake inhibitor. The lack of information on its effects in vivo prompted us to evaluate alpha(2)-adrenoceptors by means of the specific binding of [(3)H]-rauwolscine, and the 5-HT transporter (SERT) by means of the binding of [(3)H]-paroxetine ([(3)H]-Par), in platelets of depressed patients, before and after one month of treatment with trazodone (75-300 mg/day). Twenty-five outpatients of both sexes with a diagnosis of major depression, as assessed by the Structured Clinical Interview for DSM IV, were included in the study. Depressive symptoms were evaluated by means of the Hamilton Rating Scale for Depression: the total score (mean +/- SD) was 20 +/- 6 at baseline (t(0)) and 7 +/- 4 after one month of treatment (t(1)). Platelet membranes, [(3)H]- rauwolscine and [(3)H]-Par bindings were carried out according to standardized protocols. The results showed that the B(max) values of [(3)H]-Par were statistically lower at t(1) than at t(0) (733 +/- 30 vs 1471 +/- 99, P < 0.001), while the K(d) and the [(3)H]-rauwolscine binding parameters remained unchanged. The findings of this study suggest that in vivo trazodone modifies the number of the SERT proteins and that, perhaps, most of its antidepressant properties are related to this activity.

Heterogeneity of the jealousy phenomenon in the general population: an Italian study.

INTRODUCTION: Despite the general agreement that normal jealousy is heterogenous, little is known about this specific topic. METHODS: In the present study, we explored the possibility of distinguishing between four subtypes of "normal" jealousy (depressive, anxious, obsessive, and paranoid) amongst a cohort of 500 healthy university students by means of a specifically designed questionnaire, "Ouestionario della gelosia" (QUEGE). QUEGE is a self-report instrument of 30 items which explores the presence, frequency, and duration of feelings and behaviors related to jealousy. It was devised to investigate four hypothetical psychopathological profiles: depressive, paranoid, obsessive, and anxious. RESULTS: The factor analysis identified five rather than four clear-cut factors: self-esteem, paranoia, interpersonal Sensitivity, fear of being abandoned, and obsessionality. Women showed statistically significant lower levels of self-esteem and higher levels of obsessionality than men. Younger age (<25 years) was associated with lower self-esteem and higher levels of paranoia and obsessionality, while being single was associated with lower self-esteem and higher levels of obsessionality. CONCLUSION: The present study provides evidence of the reliability and validity of the QUEGE instrument, which seems to identify the presence of five psychopathological dimensions within the jealousy phenomenon in the general population.

Impulsivity, gender, and the platelet serotonin transporter in healthy subjects.

The present study explored the possible relationships between impulsivity, gender, and a peripheral serotonergic marker, the platelet serotonin (5-HT) transporter (SERT), in a group of 32 healthy subjects. The impulsivity was measured by means of the Barratt Impulsivity Scale, version 11 (BIS-11), a widely used self-report questionnaire, and the platelet SERT was evaluated by means of the specific binding of (3)H-paroxetine ((3)H-Par) to platelet membranes, according to standardized protocols. The results showed that women had a higher BIS-11 total score than men, and also higher scores of two factors of the same scale: the motor impulsivity and the cognitive complexity. The analysis of the correlations revealed that the density of the SERT proteins, as measured by the maximum binding capacity (B(max)) of (3)H-Par, was significantly and positively related to the cognitive complexity factor, but only in men. Men showed also a significant and negative correlation with the dissociation constant, Kd, of ((3)H-Par) binding, and the motor impulsivity factor. These findings suggest that women are generally more impulsive than men, but that the 5-HT system is more involved in the impulsivity of men than in that of women.

Treatment strategies for obsessive-compulsive disorder.

IMPORTANCE OF THE FIELD: In the last decades, the treatment of obsessive-compulsive disorder (OCD) has improved significantly with the introduction into the clinical practice of the selective serotonin reuptake inhibitors (SSRIs): this has led to a renewed interest in this condition and development of appropriate therapeutic strategies, including non-pharmacological techniques. AREAS COVERED IN THIS REVIEW: The aim of this paper is to present a comprehensive and critical review of pharmacological and non-pharmacological treatments usually adopted in the management of OCD. MEDLINE and PubMed (1980 - 2009) databases were searched for English-language articles by using the following keywords: OCD, clomipramine, SSRIs, resistance, predictor of response, cognitive-behavioral therapy, exposure and response prevention, repetitive transcranial magnetic stimulation, deep brain stimulation, neurosurgery, electroconvulsive therapy. WHAT THE READER WILL GAIN: The reader will gain an exhaustive review of the advantages and disadvantages of the treatments usually adopted in OCD, with a special focus on resistance and clinical features that can be used as predictors of response. TAKE HOME MESSAGE: Obsessive-compulsive disorder is a common psychiatric condition that can be adequately managed with the currently available therapeutic options. Although a certain percentage of patients do not achieve complete clinical remission, improvement of some of their core symptoms permits them to live more satisfying lives and to reach a better social adjustment.

Latest advancements on serotonin and dopamine transporters in lymphocytes.

Different data show that circulating lymphocytes possess functional serotonin and dopamine transporters (SERT and DAT, respectively). This papers aims to review most of the available literature on this topic, while highlighting the possible role of SERT and DAT, as well as that of their substrates including antidepressants on the immune system.

Alterations of the dopamine transporter in resting lymphocytes of patients with different psychotic disorders.

The aim of our study was to investigate and compare the dopamine (DA) transporter (DAT) in resting lymphocytes of 20 psychotic patients and 20 healthy control subjects, by means of both the binding parameters (Bmax and Kd) of 3H-WIN 35,428, and the reuptake parameters (Vmax and Km) of 3H-DA. The results showed that both the Bmax of 3H-WIN 35,428 binding and the Vmax of 3H-DA reuptake of the patients were significantly lower than those of healthy subjects, while the Kd or Km did not show any change. These findings, while indicating a reduced density of the lymphocyte DAT proteins, provide further support of the role of DA in psychoses and suggest that DA alterations may not be limited to brain structures.

Cognitive impairment in major depression.

In the past decade, a growing bulk of evidence has accumulated to suggest that patients suffering from major depression (MD) present some cognitive disturbances, such as impairment in attention, working memory, and executive function, including cognitive inhibition, problem- and task-planning. If the results of short-term memory assessment in depressed patients are equivocal, a general consensus exists that memory problems are secondary to attentional dysfunctions, and reflect the inability to concentrate. Moreover, both unipolar and bipolar patients show evidence of impaired verbal learning that has been commonly interpreted as reflecting an inability to transfer information from short-term to long-term storage. According to some authors, there would be a gender-related as well age-related specificity of some disturbances. Depressed patients also show impairments of executive functions and their recent exploration through brain imaging techniques has recently permitted to formulate some general hypotheses on the possible involvement of different brain areas in MD.

ABCB1 polymorphisms are associated with clozapine plasma levels in psychotic patients.

AIMS: ABCB1 is a transmembrane transporter that is expressed in excretory organs (kidneys and liver), in intestine mucosa and on the blood-brain barrier. Because of the particular distribution of the protein, the activity of ABCB1 may significantly affect drug pharmacokinetics during absorption and distribution. Of note, several SNPs of ABCB1 are known and many of them affect transporter activity and/or expression. In this view, changes in the pharmacokinetics of drugs that are ABCB1 substrates could be clinically relevant and the evaluation of ABCB1 SNPs should deserve particular attention. Therefore, the aim of the present study was to investigate the possible association between ABCB1 polymorphisms and clozapine plasma levels in psychotic patients. MATERIALS & METHODS: c.1236C>T (exon 12), c.2677G>T (exon 21) and c.3435C>T (exon 26) SNPs of ABCB1 were evaluated by PCR techniques, while plasma levels of clozapine and norclozapine were measured by HPLC in 40 men (aged, 47.6 +/- 16.6 years, median: 42 years) and 20 women (aged 40.7 +/- 11.4 years, median: 38 years) 1 month after the start of clozapine administration. RESULTS: A total of three SNPs were in Hardy-Weinberg equilibrium, with a calculated frequency of the wild-type alleles of 0.54, 0.55 and 0.45 for SNPs on exons 12, 21 and 26, respectively. Patients with c.3435CC or c.2677GG genotypes had significantly lower dose-normalized clozapine levels than those who were heterozygous or TT carriers. More interestingly, c.3435CC patients (15 subjects) needed significantly higher daily doses of clozapine (246 +/- 142 mg/day) compared with the remaining 24 CT and 21 TT patients (140 +/- 90 mg/day) in order to achieve the same clinical benefit. CONCLUSION: c.3435CC patients require higher clozapine doses to achieve the same plasma concentrations as CT or TT patients, and ABCB1 genotyping should be considered as a novel strategy that should improve drug use.

[(3)H]-YM-09151-2 binding sites in human brain postmortem.

The controversial and limited data on the distribution of dopamine (DA) receptors of type 4 (D(4)) in the human brain prompted us to explore their density and pharmacological characteristics in the prefrontal cortex, striatum and hippocampus, through a series of binding assays. Brain samples were taken during autopsy from seven subjects. Tissue homogenates were incubated with increasing concentration of [(3)H]-YM-09151-2, a D(2)-like receptor antagonist, and L-745,870 and/or sulpiride to define the non-specific binding, while PPAP was used to block sigma receptors. The results showed a low density of D(4) receptors in the hippocampus only, with a preponderance of D(2)/D(3) and sigma receptors in the prefrontal cortex and striatum. In conclusion, these findings underline that it is possible to label D(4) receptors by means of [(3)H]-YM-09151-2, provided that D(2), D(3) and sigma receptors are blocked.

Effectiveness of long-term augmentation with citalopram to clomipramine in treatment-resistant OCD patients.

INTRODUCTION: The high percentage (between 40% and 60%) of resistance to first-line drugs, such as clomipramine or selective serotonin reuptake inhibitors, is a major problem in the pharmacologic management of obsessive-compulsive disorder (OCD). In these cases, different strategies have been employed with controversial outcomes. The meager information available on the association of two serotonergic drugs prompted us to explore the possible effectiveness and tolerability of citalopram+clomipramine in resistant OCD patients. METHODS: Twenty outpatients with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnosis of OCD, who had failed to respond to at least two trials with a selective serotonin reuptake inhibitor and were currently taking clomipramine at different doses, were administered citalopram at a maximum dose of 60 mg/day. The clinical assessment was carried out at baseline (t0) and at the 4th (t1), 12th (t2), 24th (t3), 36th (t4), and 48th (t5) week by means of the Yale-Brown Obsessive Compulsive Scale, Hamilton Rating Scale for Depression, Clinical Global Impression scale, and the Dosage Record and Treatment Emergent Symptom Scale. The response was defined as a 35% decrease of the Yale-Brown Obsessive-Compulsive Scale total score. RESULTS: The results showed that approximately 50% of the patients improved significantly after 1 month of this regimen and after 1 year of treatment. CONCLUSION: This study, although carried out in a small sample and in an open fashion, represents one of the few experiences with the association of two serotonergic compounds in resistant OCD and confirms its potential usefulness and good tolerability profile. Controlled research on this association in OCD is recommended.

Decreased density of the platelet serotonin transporter in pathological gamblers.

BACKGROUND/AIMS: The aim of this study was to investigate the serotonin transporter (SERT), by means of the 3H-paroxetine ([3H]-Par) binding to platelet membranes, in patients affected by pathological gambling (PG), as compared with a similar group of healthy control subjects. METHODS: Seventeen PG patients were selected amongst those who were drug-free and at the first psychiatric interview in a Department of Addiction. The diagnosis was assessed according to DSM-IV criteria and PG severity was measured by means of the South Oaks Gambling Screen. The platelet [3H]-Par binding was carried out according to a standardized method. The binding parameters, the maximum binding capacity (B(max)) and the dissociation constant (K(d)), were obtained by means of the Scatchard analysis. RESULTS: The B(max) values of PG patients were significantly lower than that of healthy subjects, while the K(d) values were not different in the two groups. No significant effect of age, sex or psychiatric comorbidity on B(max) or K(d) was observed; there were also no correlations between clinical and biological variables. CONCLUSIONS: PG patients showed a dysfunction at the level of the platelet SERT that would suggest the involvement of the 5-HT system in this condition.

Executive function abnormalities in pathological gamblers.

BACKGROUND: Pathological gambling (PG) is an impulse control disorder characterized by persistent and maladaptive gambling behaviors with disruptive consequences for familial, occupational and social functions. The pathophysiology of PG is still unclear, but it is hypothesized that it might include environmental factors coupled with a genetic vulnerability and dysfunctions of different neurotransmitters and selected brain areas. Our study aimed to evaluate a group of patients suffering from PG by means of some neuropsychological tests in order to explore the brain areas related to the disorder. METHODS: Twenty outpatients (15 men, 5 women), with a diagnosis of PG according to DSM-IV criteria, were included in the study and evaluated with a battery of neuropsychological tests: the Wisconsin Card Sorting Test (WCST), the Wechsler Memory Scale revised (WMS-R) and the Verbal Associative Fluency Test (FAS). The results obtained in the patients were compared with normative values of matched healthy control subjects. RESULTS: The PG patients showed alterations at the WCST only, in particular they had a great difficulty in finding alternative methods of problem-solving and showed a decrease, rather than an increase, in efficiency, as they progressed through the consecutive phases of the test. The mean scores of the other tests were within the normal range. CONCLUSION: Our findings showed that patients affected by PG, in spite of normal intellectual, linguistic and visual-spatial abilities, had abnormalities emerging from the WCST, in particular they could not learn from their mistakes and look for alternative solutions. Our results would seem to confirm an altered functioning of the prefrontal areas which might provoke a sort of cognitive "rigidity" that might predispose to the development of impulsive and/or compulsive behaviors, such as those typical of PG.

Plasma and serum brain-derived neurotrophic factor (BDNF) in depressed patients during 1 year of antidepressant treatments.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) has been hypothesized to be involved in the neurobiology of major depression. The aim of this study was to assess the possible relationships between depressive symptoms and serum and/or plasma BDNF levels during 1 year of antidepressant treatment. METHODS: Plasma and serum BDNF levels were assayed in 15 drug-free depressed patients and in 15 healthy control subjects at baseline and the 1st, 3rd, 6th and 12th month of antidepressant treatment. RESULTS: At baseline, patients' serum and plasma BDNF levels were significantly lower (p<.001 and p=.004, respectively) than those found in healthy control subjects. However, while from the 1st month of treatment patients' plasma BDNF levels did not differ significantly from those observed in healthy control subjects, serum BDNF levels in patients remained significantly lower at all times. LIMITATIONS: The main limitations of the current study are represented by the small sample size and the high discontinuation rate. CONCLUSIONS: Untreated depressed patients showed reduced baseline serum and plasma BDNF levels, as compared with control subjects. The clinical improvement paralleled the normalization of plasma BDNF after 1 month of treatment, while, at every assessment time, patients' serum BDNF levels were lower than those of control subjects. This would suggest that serum BDNF might represent a non-specific trait marker of depression.

Comorbidity with axis I anxiety disorders in remitted psychotic patients 1 year after hospitalization.

INTRODUCTION: Comorbid anxiety disorders are frequently encountered in psychoses and mainly assessed during the hospitalization. METHODS: Comorbidity was investigated in 98 patients with schizophrenia, schizoaffective, or bipolar disorder, previously hospitalized for psychotic symptoms. Assessments, including Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Brief Psychiatric Rating Scale, and Clinical Global Impressions Scale, were performed during hospitalization (t0) and subsequently in a phase of remission (t1). Comorbidity was assessed at t1 only. RESULTS: One or more comorbid anxiety diagnoses were made in 46 (46.9%) patients. Of these, 15 (32.6%) received multiple anxiety diagnoses, while 31 (67.4%) single anxiety diagnoses. Schizophrenic patients had a rate of social anxiety disorder (SAD) higher (P<.05) than the others. Patients assessed with panic disorder or with obsessive-compulsive disorder at t1 showed significantly greater severity of illness at t0; patients with SAD demonstrated greater severity at t1. No significant differences in the rates of individual anxiety disorders were found in patients treated with typical or atypical antipsychotics or with both. CONCLUSION: Anxiety disorders, particularly obsessive-compulsive disorder, panic disorder and SAD, seem to be frequently comorbid in remitted psychotic patients; SAD would be more prevalent in schizophrenia and might negatively impact the course of the illness.

Romantic attachment in patients with mood and anxiety disorders.

INTRODUCTION: Romantic attachment is the establishment of a relationship with a partner and is strongly influenced by the individual's attachment style. While several studies have shown that attachment style may contribute to the development of psychopathology, less information is available for romantic attachment. The aim of the present study was to compare romantic attachment styles among patients with different mood and anxiety disorders and control subjects. METHOD: The study sample included a total of 126 outpatients, 62 of whom were affected by bipolar disorders, 22 by major depressive disorder (MDD), 27 by panic disorder, 15 by obsessive-compulsive disorder, and 126 healthy control subjects. Romantic attachment was assessed by means of the Italian version of the "Experiences in Close Relationships" (ECR) questionnaire. RESULTS: The results showed that the secure attachment style was more frequent in the control group, while the preoccupied style prevailed among the patients, with no difference among the diagnostic categories. The scores of the ECR anxiety and avoidance scales were significantly higher in the patients than in the control subjects. A trend toward higher ECR anxiety scale scores in women with panic disorder was detected, with the opposite being true for MDD. CONCLUSION: Our findings indicate that patients with different psychiatric disorders would be characterized by higher scores on both the ECR anxiety and the avoidance scales, as well as by the preoccupied style of attachment. In addition, women with panic disorder and MDD seem to be characterized by, respectively, higher and lower scores of the ECR anxiety scale than men.