Dysfunction in endocannabinoids, palmitoylethanolamide, and degradation of tryptophan into kynurenine in individuals with depressive symptoms.

BACKGROUND: The endocannabinoid (eCB) system and the serotonin (5-HT) are both implicated in the severity of the depression. 5-HT is synthesized from the amino acid tryptophan (Trp), which is also a precursor for kynurenine (Kyn) whose production is increased at the expense of 5-HT in depressed patients. No clinical studies have investigated the crosstalk between the eCB system and the Trp/5-HT/Kyn pathways. Here, we hypothesized that the eCB system is associated with an enhanced Kyn production in relation to the severity of depressive symptoms. METHODS: Eighty-two subjects (51 patients with a diagnosis of depressive disorder (DSM-5) and 31 healthy volunteers), were assessed with the Montgomery-Åsberg Depression Rating Scale (MADRS), Beck Depression Scale, and Global Clinical Impression. Serum concentrations of eCBs (N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG)); structurally related fatty acyl compounds 2-oleoylglycerol (2-OG), oleoylethanolamide (OEA), and palmitoylethanolamide (PEA); Trp, Kyn, Kyn/Trp ratio (an index of Trp degradation into Kyn) and 5-HT were also determined. RESULTS: Following a principal component analysis including the severity of depression, Kyn and the Kyn/Trp ratio appear to be directly associated with 2-AG, AEA, and PEA. Interestingly, these biomarkers also permitted to distinguish the population into two main clusters: one of individuals having mild/severe depressive symptoms and the other with an absence of depressive symptoms. Using parametric analysis, higher serum levels of 2-AG, Kyn, and the ratio Kyn/Trp and lower levels of Trp and 5-HT were found in individuals with mild/severe depressive symptoms than in those without depressive symptoms. While in asymptomatic people, PEA was directly associated to Trp, and OEA indirectly linked to 5-HT, in individuals with depressive symptoms, these correlations were lost, and instead, positive correlations between AEA and 2-AG, PEA and AEA, and PEA vs 2-AG and OEA concentrations were found. CONCLUSIONS: Parametric and non-parametric analyses suggest a possible association between eCBs, tryptophan/kynurenine biomarkers, and severity of depression, confirming a likely interplay among inflammation, stress, and depression. The enhanced relationships among the biomarkers of the 2-AG and AEA pathways and related lipids seen in individuals with depressive symptoms, but not in asymptomatics, suggest an altered metabolism of the eCB system in depression.

Association between mental health service utilisation and sharing of injection material among people who inject drugs in Montreal, Canada.

BACKGROUND: High-risk injection behaviors are associated with high prevalence of mental health problems among people who inject drugs (PWID). However, whether the use of mental health services is associated with lower risk of sharing injection material remains undetermined. This study aims to examine the association between mental health service utilisation and receptive sharing risk, and determine the potential modifying effect of psychological distress on this association. METHODS: Participants answered an interviewer-administered questionnaire at 3-month intervals gathering information on sociodemographic characteristics, substance use and related behaviors, services utilisation and significant mental health markers. Relationship between the use of mental health services and receptive sharing was modeled using the generalized estimating equation (GEE), controlling for age at baseline, gender, and other potential confounders. Psychological distress was estimated using the Kessler Psychological Distress Scale (K10). Effect modification was investigated by adding an interaction term in the univariate GEE analysis. RESULTS: 358 participants contributed to 2537 visits (median age 40.3, 82% male). Mental health service utilisation was reported in 631 visits (25%), receptive sharing in 321 visits (13%) and severe psychological distress in 359 visits (14%). In multivariate GEE analyses, a significant association was identified between receptive sharing and the use of mental health services (aOR = 0.69; 95% CI = 0.50-0.94). We found no evidence of effect modification by psychological distress. CONCLUSION: Among PWID, mental health service utilisation was associated with lower likelihood of receptive sharing, regardless of level of psychological distress. These findings should be taken into account when designing harm reduction strategies for this population.

A pilot, open-label, 8-week study evaluating desvenlafaxine for treatment of major depression in methadone-maintained individuals with opioid use disorder.

Depression is one of the most prevalent psychiatric disorders among opioid-dependent individuals. Clinical trials testing selective serotonin reuptake inhibitors among depressed patients on methadone maintenance therapy (MMT) failed to show efficacy, whereas those on tricyclic antidepressants produced mixed results with potential for cardiotoxicity. Desvenlafaxine (DESV) is a SNRI with minimal cardiotoxicity and drug interactions. This study sought to assess feasibility and tolerability of using DESV in depressed patients on MMT. A total of 18 depressed individuals on MMT received DESV (50-100 mg/day) for 8 weeks. Participants were assessed for the following: (a) Safety of DESV using Systematic Assessment for Treatment Emergent Events-GI, ECG [corrected Q-T (QTc) interval measurement] and methadone serum levels; (b) depressive symptoms using Montgomery-Äsberg Depression Rating Scale (MADRS); and (c) other outcomes including anxiety, suicidality, craving, substance use, quality of life, and other depression scales. Registration number on ClinicalTrials.gov is NCT02200406. Among participants who completed the study, MADRS scores significantly decreased at week 8 compared with baseline. Responders and remitters on MADRS at week 8 were 61 and 50%, respectively. There was no significant change in [corrected Q-T (QTc) interval measurement] between baseline and week 4. DESV was well tolerated and associated with improvement of depressive symptoms. DESV may be a promising contender to treat depression in individuals on MMT and deserves further exploration in a randomized double-blinded clinical trial.

Psychopathological and sociodemographic features in treatment-resistant unipolar depression versus bipolar depression: a comparative study.

BACKGROUND: Some authors have hypothesized that Treatment-Resistant Unipolar Depression (TRD-UP) should be considered within the bipolar spectrum disorders and that hidden bipolarity may be a risk factor for TRD-UP. However, there are neither studies comparing clinical and sociodemographic data of patients with TRD-UP versus Bipolar (BP) disorders nor are there any examining differences versus Bipolar type I (BP-I) and Bipolar type II (BP-II). METHODS: Charts analysis was conducted on 194 patients followed at the Mood Disorders Clinic of the McGill University Health Center. Sociodemographic, clinical features and depression scales were collected from patients meeting DSM-IV criteria for TRD-UP (n = 100) and BP (n = 94). Binary logistic regression analysis was conducted to examine clinical predictors independently associated with the two disorders. RESULTS: Compared to BP, TRD-UP patients exhibited greater severity of depression, prevalence of anxiety and panic disorders, melancholic features, Cluster-C personality disorders, later onset of depression and fewer hospitalizations. Binary logistic regression indicated that higher comorbidity with anxiety disorders, higher depression scale scores and lower global assessment of functioning (GAF) scores, and lower number of hospitalizations and psychotherapies differentiated TRD-UP from BP patients. We also found that the rate of unemployment and the number of hospitalizations for depression was higher in BP-I than in BP-II, while the rate of suicide attempts was lower in BP-I than in BP-II depressed patients. CONCLUSIONS: These results suggest that TRD-UP constitutes a distinct psychopathological condition and not necessarily a prodromal state of BP depression.

Antidepressant combination versus antidepressants plus second-generation antipsychotic augmentation in treatment-resistant unipolar depression.

Patients with treatment-resistant unipolar depression (TRD) are treated with antidepressant combinations (ADs) or with second-generation antipsychotics plus AD (SGA+AD) augmentation; however, the clinical characteristics, the factors associated independently with response to SGA+AD, and the outcome trajectories have not yet been characterized. We performed a naturalistic study on the latest stable trial (medication unchanged for about 3 months) in 86 TRD patients with resistance to at least two ADs trials, who received ADs (n=36) or SGA+AD (n=50) treatments. Montgomery-Asberg Depression Rating Scale (MADRS), Hamilton-Depression Rating Scale (HAM-D17), and other scales were administered before (T0) and after the latest 3-month stable trial (T3). Compared to ADs, the SGA+AD group showed increased percentage of depression with psychotic features, comorbidity for personality disorders and substance use disorders (SUD), higher number of failed ADs pharmacotherapies and depressive symptoms at T0 on all scales (P<0.001). Compared to T0, both treatments significantly decreased depressive symptoms on MADRS and HAM-D17 at T3 (P<0.001); however, the SGA+AD augmentation produced a greater decline in mean score. Logistic regression analysis indicated that psychotic features, personality disorders, and SUD were independently associated with SGA+AD treatment. Given the greater improvement in depression following SGA+AD augmentation, SGA augmentation should be indicated as a first-line treatment in severe TRD with psychotic features, SUD, and personality disorders.

Valproate augmentation in a subgroup of patients with treatment-resistant unipolar depression.

OBJECTIVES: About 50% of patients with unipolar depression suffer from treatment-resistant depression (TRD). Animal studies have suggested potential antidepressant properties of valproate (VPA) possibly due to its implication in epigenetic programming. METHODS: Fourteen TRD patients (seven males and seven females; age 19-59) received VPA (375-1000 mg/day) in addition to their treatment regimen after previously failing to respond to two or more antidepressant trials and/or different combinations. Clinical response to VPA was investigated prior the treatment (T-0) and after 1 (T-1), 4 (T-4) and 7 (T-7) months of therapy using the Montgomery-Asberg Depression Rating Scale (MADRS) and the Clinical Global Impression (CGI). RESULTS: Compared to T-0, VPA significantly decreased MADRS score at T-1 (P < 0.001), T-4 (P < 0.001) and T-7 (P < 0.001) (partial η(2)=0.86). Importantly, MADRS score at T-7 (13.6 ± 1.6, mean ± SEM) was closer to the reported value of remission (MADRS <10), and none of the patients relapsed during the observational period. Compared to T-0, VPA also decreased CGI-Severity of illness score at T-1 (p = 0.03), T-4 (p < 0.001) and T-7 (p < 0.001) (partial η(2) = 0.74). CONCLUSIONS: Antidepressant augmentation with VPA provided substantial clinical improvement and maintenance over a relatively long-term period in a subgroup of patients with severe TRD. VPA thus deserves further exploration in large double-blind clinical trials.