Interactions between grapefruit juice and psychotropic medications: an update of the literature and an original case series.

INTRODUCTION: There is a large body of preclinical data implicating that grapefruit juice (GJ) inhibits many CYP 450 isoforms. The potential of GJ-to-drug is of high relevance to clinical psychiatry, because a wide range of psychotropic medicines undergo CYP 450 metabolism and P-gp transport. AREAS COVERED: Relevant data were identified by searching the electronic databases up to February 2024. This work constitutes a summary of preclinical and clinical data on GJ impact on CYP 450 metabolism, P-glycoprotein, and organic anion-transporting polypeptides (OATPs), with focus on studies that assessed GJ-to-psychotropic drug interactions. Additionally, an unpublished case series of nine patients is provided. EXPERT OPINION: The impact of GJ on CYP 3A4 appears to be the critical mechanism for the majority of GJ-to-psychopharmacotherapy interactions described in human studies or case reports. However, there are studies and cases of patients clearly showing that this is not the only route explaining the GJ effect, and at times, this particular is of no relevance and that other CYP 450 isoforms as well as drug transporting proteins might be involved. The risk of GJ-to-psychotropic drugs needs to be further evaluated in a 'real-world' setting and apply not only measures of pharmacokinetics but also treatment effectiveness and safety.

Psychopathological symptoms in fibromyalgia and their associations with resistance to pharmacotherapy with SNRI. / Objawy psychopatologiczne w fibromialgii i ich zwiazki z opornoscia na farmakoterapie z zastosowaniem SNRI.

OBJECTIVES: Fibromyalgia (FM) is often comorbid with psychiatric disorders. Moreover, several studies show that psychiatric disorders may be linked to the severity and impact of FM. Therefore, the study described in the article had two main goals: (1) to explore various psychopathological symptom dimensions in patients with fibromyalgia and secondly, (2) to examine the links between psychopathology and response to treatment with serotonin and norepinephrine reuptake inhibitors (SNRI). METHODS: This cross-sectional study was performed between December 2020 and November 2022. The definition of resistance to SNRI was <30% reduction of pain after ≥8 weeks of treatment. 30 FM subjects responsive to SNRI (FM T[+]), 32 patients non-responsive to SNRI (FM T[-]) and 30 healthy controls were enrolled. Participants were examined by physicians and completed self-report tools to evaluate levels of depression (Quick Inventory of Depressive Symptomatology, Hospital Anxiety and Depression Scale), anxiety (State and Trait Anxiety Inventory), anhedonia (Snaith-Hamilton Pleasure Scale), bipolar symptoms (Mood Disorder Questionnaire, Hypomania Checklist), and dissociation (Dissociative Experiences Scale - Revised). ANOVA analysis and a series of simple logistic regressions were used to examine the associations between psychopathological variables and response to SNRI. RESULTS: FM T[-] vs. FM T[+] showed higher levels of: depression, state and trait anxiety and anhedonia as well as higher proportion of scores indicating the presence of anxiety disorder. Increased severity of depression, anxiety and anhedonia were predictors of resistance to SNRI. CONCLUSIONS: Modifiable psychopathological symptoms vary in FM T[+] vs. FM T[-] and are predictors of resistance to SNRI. Psychological assessment should be integrated into standard care for FM patients.

Consolidating evidence on the role of insulin resistance in major depressive disorder.

PURPOSE OF REVIEW: The circular interactions between type 2 diabetes (TMD2) and major depressive disorder (MDD) are well documented but the understanding of their mechanisms has only recently gained more clarity. Latest research indicates, that the association between TMD2 and MDD is largely mediated by insulin resistance (IR). RECENT FINDINGS: A metabolic subtype of MDD can be distinguished from other MDD subpopulations, that is characterized by predominantly atypical clinical presentation, IR and different responsiveness to antidepressant interventions. IR is a predictor of nonresponse to some antidepressants. The IR seems to be a state-marker of clinical or subclinical depression and the relationship between IR and MDD varies between sexes and ethnicities. Insulin has a direct impact on the monoaminergic systems known to underlie MDD symptoms: serotoninergic and dopaminergic, which are dysregulated in IR subjects. Several trials assessed the efficacy of insulin-sensitizing drugs in MDD with mixed results for metformin and more consistent evidence for pioglitazone and lifestyle intervention/physical activity. SUMMARY: Recently published data suggest a significant role of IR in the clinical presentation, pathophysiology and treatment response in MDD. Further research of IR in MDD and integration of existing data into clinical practice are needed.

TED-trazodone effectiveness in depression: a naturalistic study of the effeciveness of trazodone in extended release formulation compared to SSRIs in patients with a major depressive disorder.

Introduction: Selective serotonin reuptake inhibitors (SSRIs) are the most often used medications to treat major depressive disorder (MDD). Despite their effectiveness in reducing depressive symptoms, several issues are associated with their use in MDD, such as limited improvement of anhedonia, emergence of emotional blunting, induction or exacerbation of insomnia, and sexual dysfunction. Due to its also devoid of the issues related to treatment noted with SSRIs. The aim of this 12-week non-inferiority naturalistic observation was to compare the effectiveness and tolerability of SSRIs and trazodone in extended release (XR) in MDD. Methods: A total of 186 subjects were recruited, of which 92 received trazodone XR and 94 received SSRIs. Patients were allocated to trazodone XR or SSRIs, according to the attending physician based on clinical evaluation. Assessments at baseline and weeks 2, 4, 8, and 12 were conducted to evaluate the severity of depression (Montgomery-Åsberg Depression Rating Scale, clinician- and patient-rated Quick Inventory of Depressive Symptomatology-the primary endpoints of the study), anhedonia (the Snaith-Hamilton Pleasure Scale), anxiety (the Hamilton Anxiety Rating Scale), insomnia (the Athens Insomnia Scale), and therapeutic effectiveness (the Clinical Global Impression Scale). Results: After 12 weeks, trazodone XR was more effective than SSRIs in reducing the severity of depression, anxiety, and insomnia. There was a trend for higher effectiveness of in reduction of anhedonia, which became insignificant after controlling the results for the duration of previous psychiatric treatment as a covariate. The proportion of treatment-responsive subjects in the trazodone XR group compared to SSRIs was comparable or higher. The proportion of patients achieving remission was higher in the trazodone XR arm vs. the SSRI arm. Discussion: In summary, the results indicate that trazodone XR is effective in MDD in the "real-world" setting. Its potential superiority over SSRIs in addressing particular symptomatic dimensions should be verified in future studies.

Brexpiprazole-Pharmacologic Properties and Use in Schizophrenia and Mood Disorders.

In 2002, the first III generation antipsychotic drug was registered-aripiprazole. Its partial dopaminergic agonism underlies its unique mechanism of action and the potentially beneficial influence on the positive, negative, or cognitive symptoms. Due to its relatively high intrinsic activity, the drug could often cause agitation, anxiety, or akathisia. For this reason, efforts were made to develop a drug which would retain the positive favorable actions of aripiprazole but present a more advantageous clinical profile. This turned out to be brexpiprazole, which was registered in 2015. Its pharmacodynamic and pharmacokinetic profile (similarly to the other most recent antipsychotics, i.e., lurasidone or cariprazine) shows promise of increasing the effectiveness of schizophrenia treatment in the dimensions in which the previous antipsychotics were not sufficiently effective, including negative, depressive, or cognitive symptoms. Like other new antipsychotics, it can also be useful in the treatment of mood disorders, for instance drug-resistant depression. Previous reviews focused on the use of brexpiprazole in specific diagnostic groups. The aim of this article is to provide the readers with an overview of data on the mechanism of action, clinical effectiveness in all studied diagnostic groups, as well as potential drug-food interactions, and the safety of brexpiprazole.

TED-Trazodone Efficacy in Depression: A Naturalistic Study on the Efficacy of Trazodone in an Extended-Release Formulation Compared to SSRIs in Patients with a Depressive Episode-Preliminary Report.

These are the preliminary results of a 12-week non-randomized, open-label, non-inferiority study comparing the effectiveness of trazodone in an extended-release formulation (XR) versus SSRIs in the treatment of major depressive disorder (MDD). Participants (n = 76) were recruited, and 42 were assigned to the trazodone XR group and 34 to the SSRIs group. The choice of drug was based on clinical presentation and relied upon the attending physician. Assessments were made at five observation time points, at the following weeks: 0, and after 2, 4, 8, and 12 weeks. The evaluations included: symptoms of depression (MADRS, QIDS-clinician, and self-rated versions-primary study endpoints), anhedonia (SHAPS), anxiety (HAM-A), insomnia (AIS), psychosocial functioning (SDS), and therapeutic efficacy (CGI). At baseline, the trazodone group had significantly more severe depressive, anxiety, and insomnia symptoms and worse psychosocial functioning compared to the SSRIs group. After 12 weeks, trazodone XR was more effective than SSRIs in reducing the severity of insomnia and depression. There were no differences between the groups in the frequencies of therapeutic response and remission, which indicated the non-inferiority of the trazodone XR treatment. In conclusion, our results showed that in a "real world" setting, trazodone XR is effective in the treatment of patients with MDD.

TED (Trazodone Effectiveness in Depression): effectiveness of trazodone extended-release in subjects with unsatisfactory response to SSRIs. / TED (Trazodone Effectiveness in Depression): efektywnosc trazodonu o przedluzonym uwalnianiu u pacjentów z niezadowalajaca odpowiedzia na leczenie SSRI.

OBJECTIVES: Selective serotonin reuptake inhibitors (SSRIs) are the most commonly used drugs to treat major depressive disorder (MDD). However, about 50% of MDD patients do not achieve treatment response to SSRIs and there is little evidence on which drugs are effective as second-line treatment in those who do not respond to SSRIs. METHODS: In this work, the data of 79 patients with MDD were analyzed to evaluate the effectiveness of trazodone XR in the group of individuals treated de novo and those switched to trazodone XR after failed treatment attempt with SSRIs. The assessments were performed at baseline and weeks 2, 4, 8 and 12 using tools to evaluate the degree of: depression (Montgomery-Åsberg Depression Rating Scale, clinician and patient-rated Quick Inventory of Depressive Symptomatology - the primary endpoints of the study), therapeutic effectiveness (Clinical Global Impression Scale), anhedonia (Snaith-Hamilton Pleasure Scale), anxiety (Hamilton Anxiety Rating Scale), insomnia (Athens Insomnia Scale), psychosocial functioning (Sheehan Disability Scale) and sexual functioning (Female Sexual Function Inventory in women/International Index of Erectile Function in men). RESULTS: The rates of treatment response and remission were largely similar in both studied groups. CONCLUSIONS: The results showed that effectiveness of trazodone XR in the treatment of patients with MDD who did not respond to SSRIs administered as first-line treatment of a particular depressive episode was comparable to that noted in patients treated de novo. Furthermore, trazodone XR effectively improved depression, anxiety, insomnia, anhedonia and psychosocial functioning in both studied groups. Additionally, trazodone XR as secondline treatment improved sexual functions in male subjects previously treated with SSRIs.

Vortioxetine - pharmacological properties and use in mood disorders. The current state of knowledge. / Wortioksetyna ­ wlasciwosci farmakologiczne i zastosowanie w zaburzeniach nastroju. Aktualny stan wiedzy.

Vortioxetine is an antidepressant with a unique profile of receptor activity. The pharmacodynamic spectrum of vortioxetine activity is linked to the modulation of not only serotoninergic but also noradrenergic and dopaminergic transmission. At the same time, its pharmacokinetic properties determine good tolerance and safety, which are also observed in elderly patients and those burdened with somatic comorbidity. This work aims to sum up the knowledge coming from the most recent studies assessing the efficacy of vortioxetine. The efficacy of vortioxetine in the treatment of depression was confirmed in a large number of open studies, randomized controlled studies with placebo control, and meta-analyses thereof. What is more, the latest research shows that this drug allows depressed patients to achieve not only symptomatic remission but also an improvement of anhedonia and recovery in cognitive and occupational function. Furthermore, there are studies showing that vortioxetine is efficacious in the treatment of elderly patients, as well as subjects who have experienced trauma or suffer from bipolar depression. Vortioxetine is characterized by a good tolerance profile and safety; rarely does it cause severe adverse effects.

A naturalistic, 24-week, open-label, add-on study of vortioxetine in bipolar depression. / Dolaczenie wortioksetyny w terapii depresji w chorobie afektywnej dwubiegunowej ­ 24-tygodniowe, otwarte badanie naturalistyczne.

OBJECTIVES: The efficacy of vortioxetine in major depressive disorder has been evaluated in many studies. However, there is a lack of studies assessing vortioxetine in bipolar depression. METHODS: In 60 patients with bipolar depression, vortioxetine 10-20 mg daily was added to current mood stabilizing medication during 24-week, naturalistic, openlabel study. The most frequent mood stabilizers were lamotrigine, quetiapine, olanzapine, and valproates. The therapeutic efficacy was evaluated by the Clinical Global Impression - Improvement (CGI-I) and Clinical Global Impression - Severity (CGI-S) scales. Patients were classified as responding to vortioxetine when they achieved 1 or 2 points on the CGI-I scale at any stage of observation. The criterion of remission was defined as score 1 at the CGI-S. RESULTS: 73% of all patients (44/60) responded to vortioxetine and 52% (31/60) achieved clinical remission of depressive symptoms (in mean 8.97 ± 4.05 weeks). There were no significant associations between vortioxetine response/remission rates and: (1) the dose, (2) BD type, (3) clinical stage, (4) presence of rapid cycling, (5) history of psychotic symptoms, analyzed depressive symptoms, and (6) concomitantly used mood stabilizer. 4 patients (6.7%) stopped treatment due to adverse effects (nausea), and 7 patients (11.7%) discontinued treatment due to the phase switch. 14 patients (23%) experienced a loss of vortioxetine effectiveness after the initial response or remission. CONCLUSIONS: The results indicate relatively high rates of response and remission during 24-week treatment in depressed bipolar patients receiving vortioxetine concomitantly with a mood stabilizer. This may indicate that vortioxetine added to a mood stabilizer may constitute an efficient and well tolerated therapeutic option in bipolar depression.

New investigational agents for the treatment of major depressive disorder.

INTRODUCTION: Pharmacotherapy of depression is characterized by the delayed onset of action, chronic treatment requirements, and insufficient effectiveness. Ketamine, with its rapid action and long-lasting effects, represents a breakthrough in the modern pharmacotherapy of depression. AREAS COVERED: The current review summarizes the latest findings on the mechanism of the antidepressant action of ketamine and its enantiomers and metabolites. Furthermore, the antidepressant potential of psychedelics, non-hallucinogenic serotonergic modulators, and metabotropic glutamate receptor ligands was discussed. EXPERT OPINION: Recent data indicated that to achieve fast and long-acting antidepressant-like effects, compounds must induce durable effects on the architecture and density of dendritic spines in brain regions engaged in mood regulation. Such mechanisms underlie the actions of ketamine and psychedelics. These compounds trigger hallucinations; however, it is thought that these effects might be essential for their antidepressant action. Behavioral studies with serotonergic modulators affecting 5-HT1A (biased agonists), 5-HT4 (agonists), and 5-HT-7 (antagonists) receptors exert rapid antidepressant-like activity, but they seem to be devoid of these effects. Another way to avoid psychomimetic effects and achieve the desired rapid antidepressant-like effects is combined therapy. In this respect, ligands of metabotropic receptors show some potential.

Graph Analysis of Verbal Fluency Tests in Schizophrenia and Bipolar Disorder.

Verbal Fluency Tests (VFT) are one of the most common neuropsychological tasks used in bipolar disorder (BD) and schizophrenia (SZ) research. Recently, a new VFT analysis method based on graph theory was developed. Interpreting spoken words as nodes and every temporal connection between consecutive words as edges, researchers created graph structures, allowing the extraction of more data from participants' speech, called Speech Graph Attributes (SGA). The aim of our study was to compare speech graphs, derived from Phonemic and Semantic VFT, between SZ, BD, and healthy controls (HC). Twenty-nine SZ patients, twenty-nine BD patients, and twenty-nine HC performed Semantic and Phonemic VFT. Standard measures (SM) and 13 SGA were analyzed. SZ patients' Semantic VFT graphs showed lower total word count and correct responses. Their graphs presented less nodes and edges, higher density, smaller diameter, average shortest path (ASP), and largest strongly connected component than the HC group. SM did not differentiate BD and HC groups, and patients' Semantic VFT graphs presented smaller diameter and ASP than HC. None of the parameters differentiated BD and SZ patients. Our results encourage the use of speech graph analysis, as it reveals verbal fluency alterations that remained unnoticed in the routine comparisons of groups with the use SM.

Withdrawal Symptoms Following Discontinuation of Vortioxetine-Retrospective Chart Review.

The efficacy of vortioxetine has been proven in many studies, but data concerning discontinuation symptoms (DS) after vortioxetine withdrawal is scarce. The aim of our study is to systematically evaluate the prevalence, determinants, and clinical features of vortioxetine DS in a retrospective chart review. Data were obtained from medical records of 263 adult patients with depressive disorders who discontinued former vortioxetine treatment. DS were observed in eight (3%) patients after 71-375 days (median 272) of treatment. DS emerged after median three days following vortioxetine withdrawal and lasted for median seven days. The clinical presentation of DS involved: emotional lability (100% of patients), irritability (75%), sudden worsening of mood (75%), nervousness (37.5%), and agitation (37.5%). Median DESS score was four (range of four to six). DS were significantly more prevalent after accidental vs. planned discontinuation (adjusted p = 0.011) and were less frequent after switching to a different antidepressant vs. ceasing pharmacotherapy (adjusted p = 0.0165). DS appeared more often if patients discontinued therapy without medical consultation (adjusted p = 0.033). The occurrence of DS was not associated with the dose and way of drug discontinuation (sudden vs. gradual). In sum, our results show that clinicians should be aware that vortioxetine withdrawal is associated with the possibility of DS.