Placebo and nocebo effects are widely reported across psychiatric conditions, yet have seldom been examined in the context of gambling disorder. Through meta-analysis, we examined placebo effects, their moderating factors, and nocebo effects, from available randomised, controlled pharmacological clinical trials in gambling disorder.

We searched, up to 19 February 2024, a broad range of databases, for double-blind randomised controlled trials (RCTs) of medications for gambling disorder. Outcomes were gambling symptom severity and quality of life (for efficacy), and drop outs due to medication side effects in the placebo arms.

We included 16 RCTs (n = 833) in the meta-analysis. The overall effect size for gambling severity reduction in the placebo arms was 1.18 (95%CI 0.91–1.46) and for quality of life improvement was 0.63 (0.42-0.83). Medication class, study sponsorship, trial duration, baseline severity of gambling and publication year significantly moderated effect sizes for at least some of these outcome measures. Author conflict of interest, placebo run-in, gender split, severity scale choice, age of participants or unbalanced randomisation did not moderate effect sizes. Nocebo effects leading to drop out from the trial were observed in 6% of participants in trials involving antipsychotics, while this was less for other medication types.

Placebo effects in trials of pharmacological treatment of gambling disorder are large, and there are several moderators of this effect. Nocebo effects were measureable and may be influenced by medication class being studied. Practical implications of these new findings for the field are discussed, along with recommendations for future clinical trials.

No drugs are currently approved for the treatment of borderline personality disorder (BPD). These studies (a randomised study and its open-label extension) aimed to evaluate the efficacy, safety and tolerability of brexpiprazole for the treatment of BPD.

The Phase 2, multicentre, randomised, double-blind, placebo-controlled, parallel-group study enrolled adult outpatients with BPD. After a 1-week placebo run-in, patients were randomised 1:1 to brexpiprazole 2–3 mg/day (flexible dose) or placebo for 11 weeks. The primary endpoint was change in Zanarini Rating Scale for BPD total score from randomisation (Week 1) to Week 10 (timing of randomisation and endpoint blinded to investigators and patients). The Phase 2/3, multicentre, open-label extension study enrolled patients who completed the randomised study; all patients received brexpiprazole 2–3 mg/day (flexible dose) for 12 weeks. Safety assessments included treatment-emergent adverse events (TEAEs).

Brexpiprazole was not statistically significantly different from placebo on the primary endpoint of the randomised study (N = 324 randomised; N = 110 analysed per treatment group; least squares mean difference −1.02; 95% confidence limits −2.75, 0.70; p = 0.24). Numerical efficacy advantages for brexpiprazole were observed at other time points. The most common TEAE in the randomised study was akathisia (brexpiprazole, 14.0%; placebo, 1.2%); data from the open-label study (N = 199 analysed) suggested that TEAEs were transient.

The primary endpoint of the randomised study was not met. Further research on brexpiprazole in BPD is warranted based on possible efficacy signals at other time points and its safety profile.

ClinicalTrials.gov identifiers: NCT04100096, NCT04186403. Funding: Otsuka, Lundbeck.

The change in symptoms necessary to be clinically relevant in obsessive-compulsive disorder (OCD) is currently unknown. In this study, we aimed to create an empirically validated threshold for clinical significance or minimal important difference (MID).

We analyzed individual participant data from short-term, double-blind, placebo-controlled registration trials of selective serotonin reuptake inhibitors in adult OCD patients. Data were collected from baseline to week 12. We used equipercentile linking to equate changes in the Clinical Global Impression (CGI) scale to changes in the Yale-Brown Obsessive-Compulsive Scale (YBOCS). We defined the MID as the YBOCS change linked to a CGI improvement of 3 (defined as “minimal improvement”).

We included 7 trials with a total of 1216 patients. The CGI-scores and YBOCS were moderately to highly correlated. The MID corresponded to 4.9 YBOCS points (95% CI 4.4–5.4) for the full sample, or a 24% YBOCS-decrease compared to baseline. The MID varied with baseline severity, being lower in the group with mild symptoms and higher in the group with severe symptoms.

By linking the YBOCS to the CGI-I, this is the first study to propose an MID in OCD trials. Having a clearly defined MID can guide future clinical research and help interpretation of efficacy of existing interventions. Our results are clinician-based; however, there is further need for patient-reported outcomes as anchor to the YBOCS.

Alleviation of symptom severity for major depressive disorder (MDD) is known to be associated with a lagged improvement of functioning. Pharmacotherapy guidelines support algorithms for MDD treatment. However, it is currently unclear whether concordance with guidelines influences functional recovery. A guideline concordance algorithm (GCA-8) was used to measure this pathway in a naturalistic clinical setting.

Data from 1403 adults (67% female, 84% non-Hispanic/Latino White, mean age of 43 years) with nonpsychotic MDD from the Penn State Psychiatry Clinical Assessment and Rating Evaluation System registry (visits from 02/01/2015 to 04/13/2021) were evaluated. Multivariable linear regression measured associations between GCA-8 and World Health Organization Disability Assessment Schedule 2.0 (WHODAS) scores. Mediation by MDD symptom severity using the Patient Health Questionnaire depression module (PHQ-9) was also evaluated.

This study found a statistically significant improvement in WHODAS scores (functioning) between baseline and final measures (−2 points, P < .001) within one year. A one standard deviation increase in the GCA-8 score was associated with a 0.48-point reduction in mean disability score (total effect; P = .02) with significant mediation by the change in MDD symptom severity (coefficient = −0.51, P < .001) and a nonsignificant natural direct effect of the GCA-8 independent of PHQ-9 change (coefficient = −0.02, P = .92).

Higher pharmacotherapy guideline concordance is associated with better functioning for MDD patients; this association likely occurs through improvement in MDD symptom severity rather than directly.

Controlled research examining maintenance treatments for responders to acute interventions for binge-eating disorder (BED) is limited. This study tested efficacy of lisdexamfetamine (LDX) maintenance treatment amongst acute responders.

This prospective randomized double-blind placebo-controlled single-site trial, conducted March 2019 to September 2023, tested LDX as maintenance treatment for responders to acute treatments with LDX-alone or with cognitive-behavioral therapy (CBT + LDX) for BED with obesity. Sixty-one (83.6% women, mean age 44.3, mean BMI 36.1 kg/m2) acute responders were randomized to LDX (N = 32) or placebo (N = 29) for 12 weeks; 95.1% completed posttreatment assessments. Mixed-models and generalized-estimating equations comparing maintenance LDX v. placebo included main/interactive effects of acute (LDX or CBT + LDX) treatments to examine their predictive/moderating effects.

Relapse rates (to diagnosis-level binge-eating frequency) following maintenance treatments were 10.0% (N = 3/30) for LDX and 17.9% (N = 5/28) for placebo; intention-to-treat binge-eating remission rates were 59.4% (N = 19/32) and 65.5% (N = 19/29), respectively. Maintenance LDX and placebo did not differ significantly in binge-eating but differed in weight-loss and eating-disorder psychopathology. Maintenance LDX was associated with significant weight-loss (−2.3%) whereas placebo had significant weight-gain (+2.2%); LDX and placebo differed significantly in weight-change throughout treatment and at posttreatment. Eating-disorder psychopathology remained unchanged with LDX but increased significantly with placebo. Acute treatments did not significantly predict/moderate maintenance-treatment outcomes.

Adults with BED/obesity who respond to acute lisdexamfetamine treatment (regardless of additionally receiving CBT) had good maintenance during subsequent 12-weeks. Maintenance lisdexamfetamine, relative to placebo, did not provide further benefit for binge-eating but was associated with significantly better eating-disorder psychopathology outcomes and greater weight-loss.

Bipolar disorder, a chronic mental health condition characterised by fluctuations in mood, energy and functionality, affects millions of individuals worldwide. Its management requires a comprehensive approach, and, as such, treatment guidelines have a pivotal role in guiding clinicians to alleviate symptoms, prevent relapse and enhance overall patient well-being. However, the treatment landscape is far from homogenous, with significant variations existing across different countries.

This study aimed to explore and compare treatment guidelines for bipolar disorder in various regions, shedding light on the factors that influence therapeutic approaches and thus offering insights that could contribute to the ongoing refinement of evidence-based practices in management.

The study explores various international treatment guidelines for bipolar disorder that have been updated after 2014. Guidelines from the UK, Canada, Australia/New Zealand, South Korea and the International College of Neuropsychopharmacology are scrutinised to identify factors contributing to the observed differences among them.

The variations in recommended drugs across guidelines arise from the approaches employed in guideline development – whether relying on expert consensus or meta-analysis results. Timing disparities in conducting these analyses and the selection of studies also exert influence. Moreover, differences in metabolic enzymes among diverse races and the health policies implemented by individual nations play a significant part in shaping these differences.

The primary hindrance to consistent treatment conclusions lies in the scarcity of high-quality research results, leading to variations in guidelines. Enhancing evidence-based recommendations necessitates the undertaking of large-scale studies dedicated to assessing treatments for bipolar disorder.

Pharmacological treatment patterns for bipolar disorder have changed during recent years, but for better or worse?

To investigate the comparative real-world effectiveness of antipsychotics and mood stabilisers in bipolar disorder.

Register-based cohort study including all Finnish residents aged 16–65 with a diagnosis of bipolar disorder from in-patient care, specialised out-patient care, sickness absence and disability pensions registers between 1996 and 2018, with a mean follow-up of 9.3 years (s.d. = 6.4). Antipsychotic and mood stabiliser use was modelled using the PRE2DUP method and risk for hospital admission for psychiatric and non-psychiatric reasons when using versus not using medications was estimated using within-individual Cox models.

Among 60 045 individuals (56.4% female; mean age 41.7 years, s.d. = 15.8), the five medications associated with lowest risk of psychiatric admissions were olanzapine long-acting injection (LAI) (aHR = 0.54, 95% CI 0.37–0.80), haloperidol LAI (aHR = 0.62, 0.47–0.81), zuclopenthixol LAI (aHR = 0.66, 95% CI 0.52–0.85), lithium (aHR = 0.74, 95% CI 0.71–0.76) and clozapine (aHR = 0.75, 95% CI 0.64–0.87). Only ziprasidone (aHR = 1.26, 95% CI 1.07–1.49) was associated with a statistically higher risk. For non-psychiatric (somatic) admissions, only lithium (aHR = 0.77, 95% CI 0.74–0.81) and carbamazepine (aHR = 0.91, 95% CI 0.85–0.97) were associated with significantly reduced risk, whereas pregabalin, gabapentin and several oral antipsychotics, including quetiapine, were associated with an increased risk. Results for a subcohort of first-episode patients (26 395 individuals, 54.9% female; mean age 38.2 years, s.d. = 13.0) were in line with those of the total cohort.

Lithium and certain LAI antipsychotics were associated with lowest risks of psychiatric admission. Lithium was the only treatment associated with decreased risk of both psychiatric and somatic admissions.

Certain treatments have demonstrated acute efficacy for binge-eating disorder (BED) but there is a dearth of controlled research examining pharmacotherapies as maintenance treatments for responders to initial interventions. This gap in the literature is particularly critical for pharmacotherapy for BED which is associated with relapse following discontinuation. The current study tested the efficacy of naltrexone/bupropion maintenance treatment amongst responders to acute treatments for BED.

Prospective randomized double-blind placebo-controlled single-site trial, conducted August 2017–December 2021, tested naltrexone/bupropion as maintenance treatment for responders to acute treatments with naltrexone/bupropion and/or behavioral weight-loss therapy for BED with comorbid obesity. Sixty-six patients (84.8% women, mean age 46.9, mean BMI 34.9 kg/m2) who responded to acute treatments were re-randomized to placebo (N = 34) or naltrexone/bupropion (N = 32) for 16 weeks; 86.3% completed posttreatment assessments. Mixed models and generalized estimating equations comparing maintenance treatments (naltrexone/bupropion v. placebo) included main and interactive effects of acute treatments.

Intention-to-treat binge-eating remission rates following maintenance treatments were 50.0% (N = 17/34) for placebo and 68.8% (N = 22/32) for naltrexone/bupropion. Placebo following response to acute treatment with naltrexone/bupropion was associated with significantly decreased probability of binge-eating remission, increased binge-eating frequency, and no weight loss. Naltrexone/bupropion following response to acute treatment with naltrexone/bupropion was associated with good maintenance of binge-eating remission, low binge-eating frequency, and significant additional weight loss.

Adult patients with BED with co-occurring obesity who have good responses to acute treatment with naltrexone/bupropion should be offered maintenance treatment with naltrexone/bupropion.

To develop an agitation reduction and prevention algorithm is intended to guide implementation of the definition of agitation developed by the International Psychogeriatric Association (IPA)

Review of literature on treatment guidelines and recommended algorithms; algorithm development through reiterative integration of research information and expert opinion

IPA Agitation Workgroup

IPA panel of international experts on agitation

Integration of available information into a comprehensive algorithm

None

The IPA Agitation Work Group recommends the Investigate, Plan, and Act (IPA) approach to agitation reduction and prevention. A thorough investigation of the behavior is followed by planning and acting with an emphasis on shared decision-making; the success of the plan is evaluated and adjusted as needed. The process is repeated until agitation is reduced to an acceptable level and prevention of recurrence is optimized. Psychosocial interventions are part of every plan and are continued throughout the process. Pharmacologic interventions are organized into panels of choices for nocturnal/circadian agitation; mild-moderate agitation or agitation with prominent mood features; moderate-severe agitation; and severe agitation with threatened harm to the patient or others. Therapeutic alternatives are presented for each panel. The occurrence of agitation in a variety of venues—home, nursing home, emergency department, hospice—and adjustments to the therapeutic approach are presented.

The IPA definition of agitation is operationalized into an agitation management algorithm that emphasizes the integration of psychosocial and pharmacologic interventions, reiterative assessment of response to treatment, adjustment of therapeutic approaches to reflect the clinical situation, and shared decision-making.

Although antipsychotics are first-line treatments for schizophrenia, benzodiazepines (BZDs) are often used as concomitant medications in acutely exacerbated patients due to their anxiolytic and sedative effects. Cariprazine (CAR), a D3-preferring dopamine D2/D3 partial agonist antipsychotic, has been examined in many clinical studies for the treatment of acute schizophrenia, with and without benzodiazepines.

To delineate the effects of benzodiazepine-use during cariprazine treatment in acute schizophrenia.

Pooled data of cariprazine-treated (1.5-6mg/day) and placebo-treated patients from four short-term, randomised, double-blind trials (NCT00404573, NCT01104766, NCT01104779, NCT00694707) were analysed. Baseline characteristics (age, duration of illness) and efficacy outcome parameters (Total and Hostility Factor Score of the Positive and Negative Syndrome Scale [PANSS]) were compared in patients receiving benzodiazepines (for more ≥3 consecutive days) and not receiving benzodiazepines (<3 consecutive days).

Altogether, 36.7% and 40.7% of the CAR-treated and PBO-treated patients required BZDs. BZD-taking was associated with a higher age in both the CAR-treated (p=0.0002) and PBO-treated (p<0.0001) patients, and with longer illness-duration in both treatment groups (p<0.0001). PANSS Total Score at baseline was similar for BZD users and non-users (CAR: LS Mean=96.36 and 96.27; PBO: LS Mean=95.55 and 96.66). Change from baseline in the PANSS Total Score was greater for patients who did not use BZD vs those who did (CAR: LS Mean= -23.8 vs LS Mean 17.2, p<0.0001; PBO: LS Mean= -14.0 vs LS Mean 12.9, p=0.5776).

These findings may suggest that requiring benzodiazepines is a potential indicator of longer illness duration and poorer response in acute schizophrenia.

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