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Bipolar disorder affects around 2% of the population and is linked with reduced life expectancy and socioeconomic burden. Depressive episodes are difficult to treat and typically more prevalent, enduring and burdensome than manic episodes. The use of antidepressants alone has limited effect and is associated with significant clinical risk through polarity switch. Current National Institute for Health and Care Excellence guidelines recommend quetiapine, olanzapine (with or without fluoxetine) and lamotrigine; however, these medications have limited efficacy, tolerability and acceptability. The ASCEnD study aims to assess the clinical and cost-effectiveness of aripiprazole plus sertraline compared with quetiapine, offering potential improvements for outcomes in bipolar depression. The study is funded by the National Institute for Health and Care Research Health Technology Assessment programme (NIHR132773). ASCEnD is a prospective, two-arm, superiority, individually 1:1 randomised, controlled, pragmatic, parallel group, type A open-label clinical trial of aripiprazole/sertraline medication combination compared with quetiapine for bipolar depression. The study is conducted in the UK National Health Service setting with the aim of recruiting and randomising 270 participants followed-up for 24 weeks. Adults with bipolar disorder self-refer or are recruited through primary and secondary care services. The primary outcome is change in depressive symptoms 12-16 weeks after randomisation. Secondary outcomes include measures of symptom change, treatment satisfaction, tolerability, medication adherence, concomitant medication use, psychosocial functioning, quality of life and cost-effectiveness and informal carer measures of quality of life and costs of caring. The exploratory outcome is change in participant reward and punishment responsiveness. Analysis will follow a prespecified statistical analysis plan. A nested qualitative study is included to examine feasibility and acceptability of the trial design. A Clinical Trial Authorisation from Medicines and Healthcare products Regulatory Agency, and approval from the Health Research Authority (IRAS 1007468) and North East - Newcastle and North Tyneside 1 Research Ethics Committee (23/NE/0132) were obtained. Results will be disseminated through peer-reviewed publications, conference presentations and lay summaries for participants and patient and public groups. ISRCTN63917405.
The use of oral clozapine for treatment-resistant schizophrenia (TRS) is often limited by acute psychotic symptoms and medical instability. Intramuscular (IMI) clozapine has been infrequently used as a bridge to oral therapy. This literature review considers the available evidence regarding IMI clozapine's feasibility, effectiveness, and safety. A systematic scoping review with a protocol preregistered on the OSF Registry. Records extracted from Ovid MEDLINE, CINAHL, Embase, PsycInfo, Web of Science Core Collection, Scopus, CENTRAL, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, and Google Scholar. Risk of bias and quality assessments were conducted. Twenty records met the inclusion criteria, primarily consisting of case reports or series; no randomized trials were identified. Half of the included studies were rated as either "fair" or "good" quality (n=11/20). Most records addressed the initiation of clozapine in the context of oral (PO) refusal, with services describing IMI clozapine as feasible within strict governance guidelines and pharmacy support. IMI clozapine was reported to provide a bridge to PO administration, with transitions commonly occurring within days, and the use of coercive measures decreasing over time. Patient-reported data were limited; however, safety profiles mirrored those of oral clozapine; route-specific adverse effects were localized, and serious events were infrequently reported. The existing literature suggests that IMI clozapine may be used as a time-limited intervention to support continued PO administration. Further prospective studies with standardized procedures, patient-centered outcomes, and extended follow-up periods are necessary to inform clinical practice and policy development.
A dual orexin receptor antagonist, lemborexant (LEM) is widely prescribed for the treatment of insomnia, especially among patients with psychiatric disorders. However, LEM-induced nightmares may exacerbate existing psychiatric symptoms and lead to the discontinuation of treatment. Despite its still growing clinical application, few studies have identified risk factors associated with LEM-induced nightmares. The aim of this study was to elucidate the clinical factors associated with LEM-induced nightmares in clinical settings. This retrospective study included 327 psychiatric patients who were prescribed LEM at the University of Miyazaki Hospital between January 2020 and September 2024. Risk factors were identified by comparing demographic and clinical characteristics between patients who experienced nightmares (nightmare group) and those who did not (non-nightmare group). The incidence of nightmares (8.0%) exceeded the incidence reported in previous clinical trials. Multivariate logistic regression revealed that younger age (10 to 29 years), concomitant use of tandospirone, and switching from benzodiazepine drugs were significantly associated with an increased risk of nightmares. Receiver Operating Characteristic curve analysis indicated an age cutoff of ≤49 years for increased risk. Cox regression analysis further demonstrated that these factors were associated with earlier onset of nightmares following LEM initiation. This study revealed that patients aged 50 years or older who were prescribed LEM experienced a lower incidence of nightmares than younger patients. When prescribing LEM-particularly in younger patients, in combination with tandospirone, or following benzodiazepines discontinuation-clinicians should consider potential nightmares associated with LEM. These findings offer clinically meaningful insights for optimizing insomnia treatment while minimizing LEM-associated risks.
Ibogaine has garnered interest for its potential therapeutic properties in substance use and psychiatric disorders. Unlike classic psychedelics such as psilocybin or LSD, ibogaine remains underexplored in clinical research. This review aimed to synthesize the clinical literature on ibogaine use in humans over the past 3 decades, focusing on outcomes and safety. We conducted a narrative review of studies on ibogaine's clinical use published from 1990 to February 2025, including randomized controlled trials (RCTs), open-label, retrospective, and observational studies. Databases were searched for reports on efficacy and safety across various indications. Twenty-four studies and 38 case reports/series were included. Most of the positive efficacy data come from uncontrolled, open-label, or retrospective studies, many conducted in nonclinical settings, with a high risk of bias. No double-blind RCT to date has demonstrated that ibogaine or noribogaine can effectively treat opioid use disorder (OUD). Only 1 small RCT reported significant effects for cocaine use disorder. Although observational data suggest that ibogaine may alleviate symptoms of OUD, PTSD, or polysubstance dependence, these findings remain exploratory. Moreover, serious ibogaine-related adverse events have been reported, especially cardiotoxicity due to QT prolongation, which represents a considerable risk given the currently unproven efficacy. While ibogaine remains a compound of interest for neuropsychiatric research, current evidence is insufficient to support its clinical use. Further studies are needed to better demonstrate ibogaine's efficacy, optimize its safety profile, and determine how it could be integrated into psychiatric care, especially in relation to the emerging therapeutic use of classic psychedelics.
For English, the validated part of Psychedelic Experience Scale (PES48) is a four-factor structure called the Mystical Experience Questionnaire (MEQ30). The other validated part of the PES48 consists of four more factors: two more mystical factors (paradoxicality and connectedness, which together with the MEQ30 form the MEQ40), and two more non-mystical factors (visual experience and distressing experience). However, this latter four-factor part of the PES48 has thus far only been validated for the German version of the PES48. We investigated whether the overall eight-factor structure of the PES48 (which includes the MEQ30 four-factor structure) can also be validated, and thus potentially be put to good use in English. Data from 280 English PES measurements (145 different healthy participants) from four placebo-controlled studies with low to high doses of psilocybin were included. The reliability of the eight subscales was evaluated using measures of internal consistency. The validity of the factor structure was assessed through model fit indices from confirmatory factor analysis. English results were then also compared with the German PES validation data set from Stocker et al. (2024). Six of the eight subscales (mystical, positive mood, transcendence of time and space, ineffability, connectedness, distressing experience) of the English PES48 show high internal consistency, one subscale (paradoxicality) shows good, and one (visual experience) acceptable internal consistency. Both MEQ models (MEQ30 and MEQ40) show similar fits (acceptable to good model fits). In English, both MEQ models show better fits than in German. All six MEQ40 scale means of the English data are higher compared to German data. The findings suggest that the eight-factor PES48 is also a valid psychometric tool in English. With the MEQ40 part of the PES48, one can measure mystical experience with a still wider conceptual breath than with the MEQ30. Furthermore, one can also measure non-mystical visual and distressing states in an overall more comprehensive and broader conceptualization of the psychedelic experience. Higher MEQ40 scale means for the English than the German study participants could inspire future research into the role of setting in relation to mystical experience.
Background: State dissociation is commonly assessed using the Clinician Administered Dissociative States Scale (CADSS; 19-items). A briefer CADSS would have many advantages, enabling assessment of transient dissociative states and allowing repeated assessment within short intervals while minimizing participant burden. This is especially relevant in studies of dissociative drugs which cause sedation and psychomotor slowing. Here we describe the process of developing a short-form version of the CADSS (CADSS-SF), based on nitrous oxide (N2O) - induced dissociative responses in healthy volunteers.Methods: In the 'development phase', using data from three experimental pharmacological studies on N2O in healthy volunteers (n = 229), we identified the most 'N2O-responsive' items with the highest item-total correlations, endorsed by experts and consistent with published accounts on the phenomenology of drug-induced dissociation. Identified items were subjected to confirmatory factor analysis using a separate validation dataset (n = 80), which tested a series of one- and two-factor models with 6-8 items.Results: A 6-item, single-factor CADSS-SF consisted of derealization and depersonalization items and showed excellent model fit (χ2(9) = 0.246, p = .246, CFI/TLI>0.99, RMSEA = 0.059). The CADSS-SF was internally consistent (w = 0.87), correlated strongly with the full scale (r ≥ 0.88) and moderately with a measure of the related, but distinct construct of psychotomimesis (r = 0.63).Discussion: The CADSS-SF is a promising tool for rapid assessment of dissociation. It may be useful for capturing fleeting experimentally-induced dissociative phenomena that would otherwise be disrupted through the process of extended self-reporting, or for studying dissociation during drug intoxication, which is often accompanied by psychomotor slowing, sedation and inattention. The scale's brevity may allow tracking of changes in dissociation over relatively brief periods. However, like the parent long-form (19-item) CADSS, the CADSS-SF primarily captures variations in derealization/depersonalization only and may therefore be less appropriate for capturing the multidimensionality of dissociative phenomena. Further validation is required to establish the generalisability of the CADSS-SF beyond experimentally-(drug-) induced dissociation in healthy populations. Development of a short-form Clinician-Administered Dissociative States Scale (CADSS-SF), which minimizes participant burden and enables rapid assessment of drug-induced dissociation.Item selection was based on sensitivity to nitrous oxide and expert recommendation. Confirmatory factor analysis supported a unidimensional structure for CADSS-SF.CADSS-SF showed high internal consistency and strong correlation with the 19-item CADSS. Antecedentes: El estado de disociación suele evaluarse mediante la Escala de Estados Disociativos Administrada por el Clinico [Clinician-Administered Dissociative States Scale (CADSS; 19 ítems)]. Una versión más breve de la CADSS tendría múltiples ventajas, permitiendo evaluar estados disociativos relativamente transitorios y realizar evaluaciones repetidas en intervalos cortos, minimizando al mismo tiempo la carga para los participantes. Esto es especialmente relevante en estudios sobre fármacos disociativos, los cuales producen sedación y enlentecimiento psicomotor. En este trabajo describimos el proceso de desarrollo de una versión abreviada de la CADSS (CADSS-SF). Métodos: En la ‘fase de desarrollo’, utilizando datos provenientes de tres estudios farmacológicos experimentales sobre óxido nitroso (N2O) en voluntarios sanos (n = 229), identificamos los ítems con mayor respuesta al N2O, con las correlaciones ítem-total más elevadas, respaldados por expertos y consistentes con descripciones publicadas sobre la fenomenología de la disociación inducida por fármacos. Los ítems inicialmente identificados fueron sometidos a análisis factorial confirmatorio utilizando un conjunto de datos de validación independiente (n = 80), en el cual se evaluó una serie de modelos unifactoriales y bifactoriales con 6 a 8 ítems. Resultados: Una CADSS-SF unifactorial de 6 ítems mostró un excelente ajuste del modelo (χ²(9) = 0.246, p = .246, CFI/TLI>0.99, RMSEA = 0.059). La CADSS-SF fue internamente consistente (α = 0.87) fuertemente correlacionado con la escala completa (r≥0.88). Discusión: La CADSS-SF constituye una herramienta prometedora para la evaluación rápida de la disociación. Puede ser especialmente útil para captar fenómenos disociativos transitorios inducidos experimentalmente que, de otro modo, podrían verse alterados por el propio proceso de autorreporte prolongado, o para estudiar la disociación durante estados de intoxicación por drogas, los cuales suelen acompañarse de enlentecimiento psicomotor, sedación e inatención. La brevedad de la escala podría permitir el seguimiento de cambios en la disociación a lo largo de períodos relativamente breves. Sin embargo, podría ser menos adecuada para captar la multidimensionalidad de los fenómenos disociativos.
About one-third of patients fail to respond to clozapine and require augmentation. Among the various augmentation strategies, the use of long-acting injectable (LAI) antipsychotics has been evaluated in a few studies, but the data remain inconclusive. Furthermore, there is a lack of data on the use of a combination of clozapine and LAI from developed countries. This retrospective study aimed to evaluate the impact of clozapine and LAI combination on symptom profile, rehospitalization rate, and functioning in the Indian setting. For this study, treatment records of patients on clozapine were reviewed for the use of a combination of clozapine and an LAI antipsychotic. Patients who had received a combination of clozapine and LAI were included in this study. The information available in the treatment records was used to rate the patients on the clinical global improvement (CGI) scale retrospectively to evaluate the beneficial effect of the combination. Out of the 1102 patients who received clozapine while in contact with our services, 13 patients had received a combination of clozapine and an LAI. In 8 patients, LAI was started after an adequate clozapine trial, and in 5 patients, clozapine was added to the ongoing LAI antipsychotic medication. At 3 months, 12 patients were rated as "much improved," and 1 patient was rated as "very much improved" on the CGI. At the last follow-up assessment, at 6 months to 6 years, the improvement was rated as "very much improved" for 9 patients, and "much improved" for 3 patients. While on the combination, only 2 patients required further inpatient care. The combination also led to a reduction in the number of relapses and an improvement in functioning. The present study suggests that combining LAI with clozapine leads to improvement in psychopathology and functioning.
Kratom (Mitragyna speciosa) is a plant indigenous to Southeast Asia. This pilot study evaluated the pharmacodynamic (PD) effects, safety, and pharmacokinetics (PK) of kratom and several of its alkaloids. Recreational polydrug users (8 participants/cohort; 6 active: 2 placebo, N=40) completed the study. Participants had experience with opioids but were otherwise healthy. This study utilized a double-blind, between-subjects design where participants randomly received a single dose of placebo or kratom. The kratom used in the study had alkaloid levels representative of botanical kratom products (i.e., leaf) previously characterized in the literature and contained trace levels of 7-hydroxymitragynine (7-OH). The starting dose was 1 g and doses of 3, 8, 10, and 12 g were administered after safety reviews after each dose. After dosing, pupillometry and assessments of subjective effects were performed, and blood samples were collected. Safety assessments included adverse events (AE) monitoring, laboratory tests, vital signs, ECG assessments, physical examination findings, and assessment of suicidality. No deaths or serious adverse events (SAEs) occurred. Somnolence, vomiting, and nausea were the most common AEs reported. Kratom alkaloid concentrations showed generally orderly, dose-related effects. At doses ≥3 g, kratom produced pupillary constriction. Few dose-related effects were observed, although the 12 g dose of kratom produced increases on several subjective measures including ratings of "drug liking." This study investigated the safety of single-sourced botanical kratom; the results may not be representative of other kratom-containing products. Kratom produced some opioid-like effects including pupillary constriction, and the 12 g dose produced effects commonly associated with drugs of abuse such as visual analog scale (VAS) ratings of drug liking, good effects, and high.
Growing evidence links inflammation with major depressive disorder (MDD) and treatment resistance. The neutrophil-to-lymphocyte ratio (NLR) has emerged as a simple peripheral marker of systemic inflammation and immune balance and it may capture clinically meaningful heterogeneity in inflammatory burden, potentially contributing to variability in antidepressant response and vulnerability to treatment resistance. This study exploratively investigated whether baseline NLR values are associated with clinical response in patients with treatment-resistant depression (TRD) treated with intranasal esketamine in routine clinical practice. This retrospective observational study included patients with TRD treated with adjunctive intranasal esketamine at the Mood Disorder Unit of San Raffaele Hospital (Milan, Italy). Baseline NLR was calculated from complete blood count samples collected 1 to 7 days before treatment initiation. Clinical outcome was assessed after 7 months using the Clinical Global Impression-Improvement scale (CGI-I). Patients were classified as responders (CGI-I ≤2) or non-responders (CGI-I ≥3). An analysis of covariance (ANCOVA) was conducted to examine differences in baseline NLR while adjusting for age. The final sample included 16 patients (8 responders and 8 non-responders). Responders showed higher baseline NLR values compared with non-responders (1.81±0.81 vs. 1.23±0.29). After controlling for age, baseline NLR differed significantly between the 2 outcome groups (P=0.003). Higher baseline NLR was associated with sustained clinical improvement after 6 months of esketamine treatment in patients with TRD. Although preliminary and limited by the small sample size and retrospective design, these findings suggest that a patient's inflammatory status at baseline may affect their treatment response. Larger prospective studies are needed to clarify the role of inflammatory markers as predictors of response to esketamine.
While most people fully recover after mild traumatic brain injury (mTBI), a substantial minority experience persistent symptoms and incomplete recovery. This may be prevented by early interventions specifically targeting patients at risk of incomplete recovery. The UPFRONT-model was developed to identify patients at risk of poor functional outcome. This study aimed to externally validate the UPFRONT-model in an independent sample. A prospective, longitudinal, multicenter cohort study with 126 mTBI patients recruited from emergency and neurology departments (ED) of six hospitals in the Netherlands was performed. Predictors in the UPFRONT-model included educational level, Glasgow Coma Scale (GCS), neck pain at injury, alcohol intoxication, Post Traumatic Amnesia (PTA), pre-injury mental health, anxiety, depression, coping, and the number and severity of post-traumatic complaints. Functional recovery at 6 months was assessed using the Glasgow Outcome Scale Extended (GOS-E). The external validity of the UPRFONT model was assessed with measures of calibration and discrimination. The model showed acceptable discriminative ability (AUC = 0.74), comparable to the development sample (AUC = 0.77). However, calibration revealed systematic underestimation of recovery (predicted: 46%; observed: 75%), with a calibration intercept of 1.52 and a slope of 0.70. Despite differences in some predictor effects, psychological variables were robust and consistent across samples. The UPFRONT-model demonstrated solid discriminative performance in an external cohort, but tended to underestimate the likelihood of complete recovery. Further validation and optimization are needed before clinical implementation. The model holds promise for early identification of at-risk patients, enabling targeted interventions following mTBI.
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Insomnia is a symptom that can be present in many medical, psychiatric and psychological conditions, or it can occur independently as a primary disorder. Many medications are available and approved for the treatment of primary insomnia, but the evidence base for using these and other medications for treating secondary insomnia is more limited, though often under-appreciated by prescribers. This is a new algorithm from the Psychopharmacology Algorithm Project at the Harvard South Shore Program, focusing on the management of insomnia secondary to or accompanying common psychiatric disorders. The authors reviewed content from their previous algorithms for these disorders and evaluated pertinent findings from additional controlled trials, reviews, and meta-analyses, found by searches using key words of insomnia and each disorder. A detailed biopsychosocial evaluation of the patient with insomnia is the first step. Medical causes are managed. Suggested treatments for insomnia secondary to major depressive disorder include eszopiclone and trazodone, and for generalized anxiety disorder, eszopiclone and zolpidem; for post-traumatic stress disorder, consider prazosin; for bipolar manic episode, consider a second-generation antipsychotic. Patients may have more than one of these conditions, and if so, the one causing the greater disability will have priority for treatment. Conditioned insomnia, which can persist following resolution of other causes of insomnia, may also be present and nonpharmacological treatment is generally recommended. Treatment of primary insomnia, without any other psychiatric diagnosis being present, was not reviewed. Insomnia is often multifactorial. When it is secondary to psychiatric disorders, there may be evidence-supported psychopharmacology approaches rather than just targeting the insomnia solely as a symptom.
Elevating brain extracellular (active) serotonin has broad-spectrum therapeutic efficacy across multiple psychiatric indications, with relatively good safety, tolerability, and scalability. The main drugs used are the serotonin reuptake inhibitors (SRIs), originally tricyclic antidepressants (TCAs), and later mainly selective-serotonin reuptake inhibitors (SSRIs). This article reviews key clinical and ancillary animal evidence supporting that serotonin synthesis amplification adjunctive therapy can safety augments SRI clinical efficacy when SRI monotherapy is insufficient. SRIs work by blocking the serotonin transporter. This causes a net shift of serotonin to the extracellular space and increased serotonin neurotransmission, which mediates the therapeutic efficacy. However, SRI efficacy is modest, inconsistent, and with a delayed onset. Conversely, SRIs seem to elevate forebrain extracellular serotonin only modestly, inconsistently, and with a delay. Clinical trials spanning 6 decades report that SRI efficacy can be augmented by adjunctive therapy with a compound that amplifies brain serotonin synthesis, presumably acting by elevating brain extracellular serotonin beyond the SRI effect. SRI adjunctive therapy with the serotonin precursors 5-hydroxytryptophan (5-HTP) and tryptophan has been used in practice and in trials, but both compounds have poor drug properties. Adjunctive therapy with methylfolate and lithium likewise seems to augment SRI clinical efficacy at least partly through serotonin synthesis amplification. Despite this encouraging evidence, no SRI adjunctive FDA-approved drug product uses a serotonin synthesis amplification pharmacology. Such a drug could exhibit general SRI-augmentation therapeutic potential and be scalable across clinical scenarios.
To evaluate MK-1942, a negative allosteric modulator of mGluR2, for treatment-resistant depression using chronic and intermittent dosing. Randomized, double-blind, 4-week study of MK-1942 added to stable antidepressant therapy in adults with treatment-resistant depression (NCT04663321). Participants were randomized 2:1:2 to (1) daily MK-1942 titrated from 5 to 20 mg bid, (2) twice-weekly MK-1942 10 mg, or (3) placebo. The endpoints were Montgomery Asberg Depression Rating Scale (MADRS) scores at week 3 (daily MK-1942) and week 1 (twice-weekly MK-1942). The study was terminated following asymptomatic elevations in liver function tests. At termination, ~70% of the planned enrolment was achieved (MK-1942 daily N=40, MK-1942 twice-weekly N=19, placebo N=40). No significant efficacy differences from placebo were seen for either MK-1942 group. The difference in mean change-from-baseline MADRS score for daily MK-1942 vs placebo directionally favored placebo at Week 3 (3.3 [95% CI: -1.4, 8.0]) and all other time points. The difference between twice-weekly MK-1942 and placebo directionally favored placebo at week 1 (1.9 [95% CI: -2.7, 6.4]) but not at later time points (eg, week 4, -1.5 [95% CI: -8.0, 4.9]). Interestingly, at every time point, the difference between twice-weekly and daily MK-1942 directionally favored the twice-weekly group. Discontinuations due to an adverse event were more common with MK-1942 than placebo (daily=10.0%, twice-weekly=15.8%, placebo=2.5%), and dizziness was the most common adverse event (daily=25.0%, twice-weekly=31.6%, placebo=7.5%). Although interpretation of the findings is limited by the early termination of the trial, MK-1942 was not effective in treatment-resistant depression.
The aim of this study was to describe pharmacological prescribing patterns for major depressive disorder (MDD), particularly regarding the use of atypical antipsychotics (AAPs) for the treatment of MDD, and the underlying factors that may influence decision-making. An electronic cross-sectional survey with 210 health care professionals (HCPs) involved in the treatment of MDD in 4 countries [United States (57), Canada (53), Brazil (39), Japan (61)] was conducted in May 2024 to July 2024. Of the total HCPs, 62.9% (n = 132) were psychiatrists, 31.9% (n = 67) primary care physicians or general practitioners, and 5.2% (n = 11) nurse practitioners or physician assistants. Selective serotonin reuptake inhibitors (SSRIs) were the most commonly prescribed first-line antidepressants across all countries surveyed. Regardless of disease severity, the first step for patients with inadequate response to the first antidepressant treatment was reported to be switching to another antidepressant (mild MDD: 66.7%, moderate MDD: 56.2%, severe MDD: 41.0%). Overall, SSRIs were the most common treatment class, typically augmented with AAPs, followed by serotonin-norepinephrine reuptake inhibitors. HCPs across the countries surveyed increasingly utilized augmentation with AAPs as the severity of MDD increased, with the severity of the current depressive episode and the number of prior antidepressants being the most important patient and treatment factors, respectively, in this decision. In addition, symptom domains, particularly underactive noradrenergic/norepinephrinergic activity and anxiety, were deemed crucial by HCPs in later treatment lines. The study highlighted complex treatment paradigms in MDD and the need for alternative therapeutic strategies and more tailored options that specifically target receptor pharmacology.
Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by motor, neuropsychiatric, cognitive, and peripheral alterations impairing functional capacity and quality of life (QoL). Pharmacotherapies, including dopaminergic and glutamatergic drugs, primarily target motor symptoms, while cholinergic modulators address cognitive decline. However, the literature lacks comprehensive reviews evaluating the combination of these three drug classes across a broad spectrum of clinical outcomes, extending beyond the total motor score (TMS). This systematic review aimed to assess the efficacy of dopaminergic, glutamatergic, and cholinergic drugs on motor, functional, cognitive decline, and QoL in HD patients. Following PRISMA guidelines, searches were performed in MEDLINE, Embase, Scopus, Web of Science, and the Cochrane Library until October 2025. Randomized clinical trials evaluating these three classes of drugs in adults with genetically confirmed HD were included. Primary outcomes were Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score (TMS), Total Functional Capacity (TFC), and cognitive performance. Secondary outcomes included the Independence Scale (IS) and QoL. Risk of bias was assessed using the Cochrane RoB 2 tool. Due to substantial heterogeneity, results were synthesized descriptively. From 32,746 studies, 15 were included in the final analysis. Findings showed that UHDRS TMS was improved with dopaminergics (tetrabenazine, deutetrabenazine, and pridopidine) and glutamatergic (riluzole) drugs. Only pridopidine treatment exhibited efficacy on UHDRS TFC, subsequently improving UHDRS IS. For QoL, deutetrabenazine treatment proved effective. In the UHDRS cognitive domain, tetrabenazine improved performance in the Stroop Color and Word test, while rivastigmine (cholinergic) improved verbal fluency. Dopaminergic, glutamatergic, and cholinergic drugs exhibit distinct efficacy profiles across various motor and non-motor UHDRS components. This positions them as therapeutic options for attenuating both the motor and non-motor symptoms in HD.
Chronic insomnia causes malaise and is associated with depression, irritability, cognitive impairment, impaired alertness, and substance abuse. Individuals with posttraumatic stress disorder (PTSD) often have both inadequate and fragmented sleep, putting them at elevated risk for these consequences. Sleep abnormalities in patients with PTSD include frequent trauma-related nightmares, prolonged sleep latency, frequent interruptions, early awakening, nighttime behavioral disorders, and disruptions of sleep cycles. Here, we review the pharmacological treatment for nightmares with an emphasis on noradrenergic (NA) signaling, following the clinical observation that medication treatment with alpha-1 adrenergic blocking agents, such as prazosin, improves nightmares. We discuss the randomized controlled trials (RCTs) examining prazosin's impact on nightmares, including its efficacy and safety, and the limitations of the studies. In addition, we review the accumulating evidence from case reports, chart review, and small studies for several other anti-alpha-1 agents (specifically doxazosin, terazosin, and tamsulosin) and their efficacy in treating nightmares in PTSD. RCT studies for prazosin suggest clinical efficacy for PTSD-related nightmare disorder in subpopulations of individuals with this condition. Case studies, pilot, and open label trails suggest possible clinical use of terazosin, tamsulosin, and doxazosin in PTSD-related nightmares, however, further RCTs are needed. When available and clinically tolerated, prazosin continues to have the best evidence base for use in PTSD-related nightmares. When prazosin use is not feasible, alternative alpha-1 blockers may be effective in a subset of patients.
Continuation treatment with sertraline plus olanzapine is associated with lower risk of relapse of remitted psychotic depression than sertraline plus placebo. We examined the effect of continuation pharmacotherapy on health-related quality of life (HRQOL) in remitted psychotic depression. One hundred and twenty-six men and women, aged 18 to 85 years, who had achieved sustained remission of psychotic depression with open-label treatment with sertraline plus olanzapine were randomized to continue sertraline plus either olanzapine or placebo. HRQOL was measured with the 36-item Short Form Health Survey (SF-36) at randomization baseline and study termination. The primary outcome was change in each of the eight SF-36 domains. Linear regression examined the relationship between randomized treatment and change in SF-36 domain scores. Sertraline plus olanzapine was associated with better outcomes in the Role Emotional (RE) and Mental Health (MH) domains than sertraline plus placebo. Relapse was associated with marked decline in both RE and MH scores. RE and MH scores at study termination were more than two standard deviations below the population mean in approximately one quarter of participants in the sertraline plus placebo group. In individuals with remitted psychotic depression, continuation treatment with sertraline plus olanzapine was associated with better outcomes in HRQOL domains directly relevant to mental health than treatment with sertraline plus placebo. These findings suggest that the benefit of sertraline plus olanzapine in preventing relapse of psychotic depression is associated with benefit in HRQOL.
Decision trees can use clinical predictors to determine whether to continue the same antidepressant or switch to a different treatment in older patients with major depressive disorder (MDD). We examined whether pharmacogenetic and pharmacokinetic variables could improve their performance. We analyzed 191 participants from the Incomplete Response in Late-Life Depression: Getting to Remission (IRL-Grey) trial who had not responded fully after 4 weeks of venlafaxine XR (150 mg/d) and for whom venlafaxine up to 300 mg/d was continued for 8 additional weeks. CYP2D6 genotypes were determined; venlafaxine, o-desmethylvenlafaxine (ODV), and active moiety (AM) exposures at week 4 were calculated using population pharmacokinetic modeling. Decision tree analysis was performed using 5 early clinical predictors of eventual nonresponse identified in previous research and 4 pharmacogenetic and pharmacokinetic potential predictors. One decision tree was designed to optimize specificity (k=0.3), and another to optimize sensitivity (k=0.7). Longer episode duration and lack of partial response at week 4 were retained as clinical predictors, and lower AM and ODV exposures were identified as additional predictors. Negative predictive values (NPVs) of the high-specificity and high-sensitivity trees (77.7% and 73.0%, respectively) were similar to NPVs in trees based solely on clinical predictors. Our methods can guide future studies combining clinical and biomarker data to address applied pharmacological questions relevant to day-to-day practice.