Difficult-To-Treat Depression. Scoping Review.

Objective: Recently, several academics have recommended that the concept of difficult-to-treat depression (DTD) should be considered in some of the cases where achieving or maintaining remission of depressive symptoms is not possible. In 2020, a consensus statement, not based on a formal process and systematic review defined difficult-to-treat depression as "depression that continues to cause significant burden despite normal treatment efforts". In addition to addressing symptom control, interventions for DTD should also target other factors, including the management of psychiatric and medical comorbidities, psychosocial functioning, self-esteem, and self-management strategies. The purpose of this scoping review is to explore the scientific literature, which is still unclear and vague, regarding the pathophysiology and treatment of difficult-to-treat depression, providing a summary of its current conceptualization. This represents a cultural and scientific shift that offers clinicians and researchers valid and up-to-date study criteria, thus expanding upon the model of treatment-resistant depression (TRD). Consequently contributions, concepts, theories and gaps of the state of the art in the description of difficult-to-treat depression have been summarized here. Method: A research study was conducted using PubMed, Scopus, PsycINFO, Cochrane Library, and Open Grey databases to identify and examine articles reporting key features related to the recent concept of difficult-to-treat depression. The research covered a period of time between January 1, 2013, and March 1, 2023. Based on a formal checklist, two researchers independently assessed the eligibility criteria to determine which studies to include or exclude in this search. Further data evaluations were conducted for the articles that were deemed to have the most comprehensive descriptions. Results: The results of the research yielded a body of literature that provides a clear definition of difficult-to-treat depression and insights into its clinical application and research perspective. Conclusions: DTD represents a cultural and scientific shift that provides clinicians and researchers with valid and up-to-date study criteria that allow the extension of the treatment-resistant depression (TRD) model. The main difference lies in the operational process of assessment and intervention in the depressive syndrome in relation to the search for a therapeutic response. The results of this review show that DTD is a theoretically and clinically useful conceptualization for depressive syndromes that are not just simply resistant to treatment. This clinical condition entails a novel clinical therapeutic approach for specific patients and may be used throughout the world to help recognize this clinical condition while optimizing overall care for these patients. However, as we have highlighted, in the absence of RCTs and further observational studies, it is desirable that DTD be further investigated and defined..

[Treatment-resistant depression. From classification to new therapies.] / Depressione resistente a trattamento. Dalla classificazione alle nuove terapie.

AIMS: This paper aims to investigate the advances in recent years in the recognition and therapy of treatment-resistant depression starting from the concepts of: depressive disorder, resistance and pseudoresistance to drug treatment in depression, and appropriate treatments of treatment-resistant depression. METHODS: An extensive research was carried out on scientific databases such as: PubMed, PsychInfo and Cochrane Library, until May 2022, using the keywords "major depression", "treatment-resistant depression", "staging", "instrumental therapies for resistant depression", "esketamine" and "psilocybin". RESULTS: Subjects who do not respond to antidepressants show a form of treatment resistance that requires an approach with additional pharmacological and/or instrumental therapies. Recently, esketamine and psilocybin are of particular interest among clinicians, and instrumental treatments such as: vagus nerve stimulation, deep brain stimulation, repetitive transcranial magnetic stimulation, transcranial direct current stimulation, epidural cortical stimulation, and electro convulsive therapy, are being added to them. DISCUSSION AND CONCLUSIONS: Treatment-resistant depression has increasingly become a public health problem due to the significant number of relapses, hospitalizations and mortality it entails, with increased demand for the use of more drugs, therapeutic resources by health services, and loss of quality of life for patients. Treatment-resistant depression needs to be addressed through the creation of dedicated study protocols. Future research should focus on the need to establish operational, valid and appropriate criteria, both on the psychopathological, clinical governance and therapeutic levels, focusing on the latest therapies in order to provide reliable data on the benefits, risks and costs associated with their use.

Implicit memory in schizophrenia: a meta-analysis.

OBJECTIVE: Previous studies examining implicit memory in schizophrenia yielded inconsistent results. The present meta-analysis aimed at determining whether, compared to healthy controls, schizophrenic patients: (a) exhibited reduced priming in the whole set of studies; (b) were differentially impaired in conceptual/perceptual and production/identification tests; and (c) were less efficient in the use of semantic encoding processes. METHOD: A systematic search in PsycINFO and PubMed led to the selection of 22 critical studies (31 effect sizes), comparing repetition priming in 836 schizophrenic patients and 760 healthy controls. Moderators were assessed by classifying implicit tasks into the perceptual/conceptual and identification/production categories, and by distinguishing between perceptual and conceptual encoding instructions. RESULTS: Overall, implicit memory was slightly, but significantly, impaired in schizophrenia (d=0.179). Patients exhibited reduced priming in conceptually-driven tasks (d=0.447), but intact priming in perceptually-driven tasks (d=0.080). No significant difference was observed between identification and production priming (d=0.064 vs. d=0.243). Finally, priming in schizophrenic patients was significantly lower than that of controls when the encoding task required the analysis of the conceptual properties of the stimuli (d=0.261). CONCLUSION: Results suggest that schizophrenia is associated with a specific deficit in the use of conceptual processes, both at encoding and at retrieval. In contrast with theoretical expectations, high levels of response competition did not disproportionately impair the patients' performance.

Testing the Identification/Production Hypothesis of Implicit Memory in Schizophrenia: The Role of Response Competition.

OBJECTIVES: Previous evidence indicates that patients with schizophrenia exhibit reduced repetition priming in production tasks (in which each response cue engenders a competition between alternative responses), but not in identification tasks (in which each response cue allows a unique response). However, cross-task comparisons may lead to inappropriate conclusions, because implicit tests vary on several dimensions in addition to the critical dimension of response competition. The present study sought to isolate the role of response competition, by varying the number of solutions in the context of the same implicit tasks. METHODS: Two experiments investigated the performance of patients with schizophrenia and healthy controls in the high-competition and low-competition versions of word-stem completion (Exp.1) and verb generation (Exp.2). RESULTS: Response competition affected both the proportions of stems completed (higher to few-solution than to many-solution stems) and the reaction times of verb generation (slower to nouns having no dominant verb associates than to nouns having one dominant verb associate). Patients with schizophrenia showed significant (non-zero) priming in both experiments: crucially, the magnitude of this facilitation was equivalent to that observed in healthy controls and was not reduced in the high-competition versions of the two tasks. CONCLUSIONS: These findings suggest that implicit memory is spared in schizophrenia, irrespective of the degree of response competition during the retrieval phase; in addition, they add to the ongoing debate regarding the validity of the identification/production hypothesis of repetition priming.

Is conceptual implicit memory impaired in schizophrenia? Evidence from lexical decision and category verification.

INTRODUCTION: Implicit memory tasks differ along two orthogonal dimensions, tapping the relative involvement of perceptual/conceptual and identification/production processes. Previous studies have documented a dissociation between perceptual (spared) and conceptual (impaired) implicit memory, using in the latter case a production task (category exemplar generation), in which there is high response competition during the retrieval phase. The present study sought to determine whether the perceptual/conceptual dissociation held when comparing two identification tasks, in which there is no response competition at retrieval. METHODS: In two experiments, repetition priming was assessed in 44 schizophrenic patients and 46 healthy controls in lexical decision (a test based on perceptual identification processes) and category verification (a test based on conceptual identification processes). RESULTS: Schizophrenic patients achieved a priming as high as that of controls in the lexical decision task. In contrast, only controls exhibited significant priming in the category verification task. CONCLUSIONS: It is concluded that schizophrenia is associated with a specific deficit in conceptual implicit memory, irrespective of the degree of response competition in the test phase.

The attentional boost effect in schizophrenia.

The present study reports 2 experiments examining the Attentional Boost Effect (ABE) in schizophrenic patients and matched healthy controls, using visual and verbal materials. The ABE refers to the surprising finding that, in a divided attention condition, images and words encoded with targets are remembered better than images and words encoded with distractors. Unlike controls (who showed the typical ABE), schizophrenic patients reported no memory advantage for stimuli presented together with targets in the divided attention condition. On the other hand, the interference effect on the recognition of stimuli presented with distractors was not exacerbated in patients (as compared with controls). In line with the dual-task interaction model proposed by Swallow and Jiang (2013), the absence of a significant facilitation indicates that schizophrenic patients have a deficit in the process of attentional enhancement triggered by target detection. A number of neural mechanisms potentially underlying this impairment are discussed, as well as implications for the characterization of the attentional deficits involved in schizophrenia.

Memory for symmetry and perceptual binding in patients with schizophrenia.

The present study investigated the use of perceptual binding processes in schizophrenic (SC) patients and matched healthy controls, by examining their performance on the recall of symmetrical (vertical, horizontal and diagonal) and asymmetrical patterns varying in length between 2 and 9 items. The results showed that, although SC patients were less accurate than controls in all conditions, both groups recalled symmetrical patterns better than asymmetrical ones. The impairment of SC patients was magnified with supra-span symmetrical arrays, and they were more likely to reproduce symmetrical patterns as asymmetrical, particularly at medium and high length levels. Hierarchical regression analyses further indicated that the between-group differences in the recall of supra-span vertical and horizontal arrays, which require a greater involvement of visual pattern processes, remained significant after removing the variance associated with performance on asymmetrical patterns, which primarily reflects intrafigural spatial processes. It is proposed that schizophrenia may be associated with a specific deficit in the formation and retrieval of the global visual images of studied patterns and in the use of the on-line information about the type of symmetry being tested to guide retrieval processes.

Intramuscular aripiprazole in the acute management of psychomotor agitation.

STUDY OBJECTIVE: To assess acute efficacy and safety of 9.75 mg of intramuscular (IM) injections of the atypical antipsychiatric aripiprazole in patients with schizophrenia or bipolar disorder and acute agitation. DESIGN: Open-label trial of IM injections of aripiprazole and 24-hour monitoring of clinical response in patients with major psychoses and acute agitation. Partial analysis of blood levels of the administered drug to correlate with clinical response. SETTING: Acute psychiatric care wards in a single university hospital. PATIENTS: A total of 201 acutely agitated patients (79 with schizophrenia and 122 with bipolar disorder I). INTERVENTION: Aripiprazole 9.75 mg IM injection. MEASUREMENTS AND MAIN RESULTS: We evaluated clinical response using the Excitatory Component of the Positive and Negative Syndrome Scale (PANSS-EC), the Agitation/Calmness Evaluation Scale (ACES), and the Clinical Global Impressions scale (CGI). Assessments were conducted 30, 60, 90, and 120 minutes and 24 hours after the first injection for PANSS-EC and ACES, and 2, 4, 6, and 24 hours for CGI. Response was at least a 40% decrease in PANSS-EC scores. We measured serum aripiprazole and dehydroaripiprazole levels in a subsample. IM aripiprazole significantly improved clinical measures. PANSS-EC improved progressively, starting after 30 minutes. ACES improved after 90 minutes and continued thereafter. Effects were sustained, with steadily decreasing CGI scores, until the 24th hour. Response rate was 83.6% after 2 hours, but with repeat injections, it rose to over 90% with no differences among diagnostic groups. Although there were gender differences in the response to individual PANSS-EC items, the responses were similar overall. Neither clinical monitoring nor patient reporting revealed any side effects. No therapeutic window was identified, and levels did not correlate with any clinical measure. CONCLUSION: Aripiprazole was effective and safe in reducing acute agitation in patients with bipolar disorder or schizophrenia. Our results compare favorably to double-blind trials, probably due to higher expectations in trials involving no placebo arm. Absence of side effects could be related to the short observation time.

An improved simple LC-MS/MS method for the measurement of serum aripiprazole and its major metabolite.

BACKGROUND AND OBJECTIVES: Current liquid chromatographic tandem mass spectrometry (LC-MS/MS) methods to measure serum levels of aripiprazole (Ar) and dehydroaripiprazole (DHAr) are sensitive, but difficult to use in a hospital context. We aimed to develop a rapid LC-MS/MS method allowing reliable level measurement in the presence of co-administered drugs, withdrawing samples from 22 patients with acute agitation receiving 9.75 mg aripiprazole IM injection. METHOD: We developed a sensitive and selective HPLC-MS/MS method to measure serum Ar and DHAr levels in a hospital laboratory, requiring minimal sample preparation and inferior sample volume compared to previous LC-MS/MS methods. Analytes were separated on a reversed-phase HPLC (run-time, 10 min). A triple quadrupole tandem mass spectrometer was used for quantitative analysis in positive mode by a multiple reaction monitoring. Samples were drawn 2, 4, 6, and 24h post-injection. RESULTS: Calibration curves (2-1000 ng/mL for Ar and 3.5-500 ng/mL for DHAr) were linear, with mean correlation coefficient >0.9998. Within- and between-day precision and accuracy were within 10%. Mean recovery was 95.2 ± 4.5% for Ar and 97.6 ± 7.2% for DHAr. Ar and DHAr peaks were not affected by other co-administered psychotropic drugs. CONCLUSION: Our method measured Ar and DHAr concentrations reliably, simply and rapidly without employing many reagents, as currently existing methods.