BACKGROUND:Like ketamine, group II metabotropic glutamate receptor (mGluR2/3) antagonists increase glutamate release and monoaminergic signaling, promote synaptic plasticity, and show antidepressant-related activity in preclinical models. A recent phase I trial of the orthosteric mGluR2/3 antagonist prodrug TS-161 established its safety, tolerability, and pharmacokinetic profile. METHODS:This phase IIa randomized, placebo-controlled, double-blind, crossover, proof-of-concept, single-site trial was designed to evaluate the antidepressant effects of TS-161. Eleven unmedicated adults with treatment-resistant depression received either oral TS-161 (50 to 100 mg daily) or a placebo for 3 weeks before crossing over to the other condition. The study was halted early due to low recruitment. RESULTS:Adverse events were mild and consistent with the prior phase I study. Linear mixed models using drug×time interaction to estimate mean Montgomery-Åsberg Depression Rating Scale scores per treatment identified no significant difference between treatment conditions at any timepoint, including the primary endpoint, day 21 (P=0.91). One of the 11 participants responded to TS-161 by day 7 (vs. 0/9 receiving placebo); no participants achieved remission. Magnetic resonance spectroscopy suggested a qualitative trend for increased glutamate metabolite values, and TS-161 increased gamma power during magnetoencephalography relative to baseline and placebo (pFDR<0.01) in lateral cortical regions. Peripheral brain-derived neurotrophic factor levels trended toward elevation (overall drug effect P=0.055). No advantages were seen in secondary clinical or cognitive outcomes. CONCLUSIONS:The findings suggest potential central nervous system engagement through proxy biomarkers and increased glutamatergic tone, but this did not translate to clinical improvement.
BACKGROUND:Double-blind, placebo-controlled trials are often affected by higher-than-anticipated placebo responses that may contribute to study failure. It is common to observe symptomatic improvement immediately after randomization regardless of treatment allocation. METHODS:This post hoc analysis examined the early randomization effect in a recent 4-week double-blind, placebo-controlled study that examined a novel presynaptic mGluR2 inhibitor, MK-1942, in a daily or twice-weekly dosing strategy versus placebo as an adjunctive treatment in acutely depressed participants with major depressive disorder who had not adequately responded to antidepressant treatment. RESULTS:The original study failed to meet its primary endpoints, but a post hoc analysis revealed an early randomization effect that may have impeded signal detection. Over 60% of the overall Montgomery Asberg Depression Rating Scale (MADRS) score improvement observed in the placebo group occurred within the first week of this 4-week study, and >20% of placebo-assigned participants met criteria as treatment responders within 1 week after randomization. Using week 1 as an alternative ("revised") baseline, the percentage of placebo responders at week 4 was reduced from 48.6% to 31.4%. Cohen standardized effect size favoring the twice-weekly MK-1942 dosing over placebo improved from -0.33 (original baseline) to -0.54 at week 4 by applying the revised baseline. CONCLUSIONS:These post hoc results suggest an early randomization effect may complicate the interpretation of studies that examine treatment effects of drugs in development. Masking the timing of randomization with blinded, placebo-lead-in designs may warrant consideration for depression studies, particularly for rapid-acting antidepressants.
BACKGROUND:Obsessive-compulsive symptoms are frequently observed in patients with bipolar disorder and present a significant therapeutic challenge. This study evaluated the efficacy and safety of memantine as an adjunctive therapy for obsessive-compulsive disorder in patients with bipolar disorder. METHODS:In this randomized, double-blind, placebo-controlled trial, 46 patients with bipolar disorder and obsessive-compulsive disorder, stabilized on quetiapine and lithium, were randomly assigned to receive either memantine (n = 23) or placebo (n = 23) for 6 weeks. RESULTS:The memantine group showed a significant reduction in Yale-Brown Obsessive-Compulsive Scale scores compared with the placebo group (Cohen d = 1.57 vs 0.42, P < 0.001). Nausea was the most common side effect, but overall adverse effects were minimal. CONCLUSION:Memantine appears to be a safe and effective adjunctive treatment for obsessive-compulsive disorder in patients with bipolar disorder, warranting further investigation.
PURPOSE:Aripiprazole, cariprazine, and brexpiprazole are third-generation antipsychotics indicated for the treatment of various mental health conditions. Several cases of gambling-related harms and various impulse control problems related to aripiprazole have been reported. The objective of our study was to conduct a comprehensive review focusing on case reports about gambling disorder induced by partial dopamine agonist therapy. PROCEDURES:A multistep literature search in different databases was carried out. Articles were screened by title and then by abstract for inclusion in data extraction. Articles were included if they were: (1) providing data about gambling behaviour induced by a partial dopamine agonist, (2) case reports or case series, and (3) written in English. FINDINGS:Seventeen articles were eligible for data extraction, for a total of 36 patients. All the case reports were related to aripiprazole, while no case studies reporting gambling induced by brexpiprazole and cariprazine were found. The mean age of the total sample was 35.1 years (range: 17 to 64). The main psychiatric comorbidities were schizophrenia (N = 15, 41.6%), followed by bipolar disorder (N = 7, 19.4%). In most of the cases, it was necessary to suspend aripiprazole, with a good outcome on gambling disorder (N = 24, 66.6%). IMPLICATIONS:The data presented suggest a clear relationship between aripiprazole and gambling behaviour, although more research is needed on this topic. Clinicians should be aware of the risk of gambling associated with partial dopamine agonists, and should therefore monitor the occurrence of gambling behaviour when introducing this drug, because patients may be reluctant to disclose it voluntarily.
Purpose: Aripiprazole, cariprazine, and brexpiprazole are third-generation antipsychotics indicated for the treatment of various mental health conditions. Several cases of gambling-related harms and various impulse control problems related to aripiprazole have been reported. The objective of our study was to conduct a comprehensive review focusing on case reports about gambling disorder induced by partial dopamine agonist therapy. Procedures: A multistep literature search in different databases was carried out. Articles were screened by title and then by abstract for inclusion in data extraction. Articles were included if they were: (1) providing data about gambling behaviour induced by a partial dopamine agonist, (2) case reports or case series, and (3) written in English. Findings: Seventeen articles were eligible for data extraction, for a total of 36 patients. All the case reports were related to aripiprazole, while no case studies reporting gambling induced by brexpiprazole and cariprazine were found. The mean age of the total sample was 35.1 years (range: 17 to 64). The main psychiatric comorbidities were schizophrenia (N = 15, 41.6%), followed by bipolar disorder (N = 7, 19.4%). In most of the cases, it was necessary to suspend aripiprazole, with a good outcome on gambling disorder (N = 24, 66.6%). Implications: The data presented suggest a clear relationship between aripiprazole and gambling behaviour, although more research is needed on this topic. Clinicians should be aware of the risk of gambling associated with partial dopamine agonists, and should therefore monitor the occurrence of gambling behaviour when introducing this drug, because patients may be reluctant to disclose it voluntarily.
OBJECTIVE:Unintentional lithium toxicity is a clinically relevant and potentially underrecognized complication in patients with bipolar disorder receiving long-term maintenance therapy. This literature review aimed to synthesize published case reports of unintentional lithium toxicity in bipolar disorder, focusing on recurrent clinical manifestations, contributing risk factors, and the relationship between clinical toxicity and serum lithium concentrations. METHODS:Case reports published between 2009 and 2024 were identified through PubMed and the Virtual Health Library using the terms lithium, intoxication, and bipolar disorder. Adult patients with bipolar disorder experiencing unintentional lithium toxicity were included. Demographic data, clinical presentation, serum lithium concentrations, renal function, comorbidities, duration of lithium therapy, and concomitant medications were extracted and descriptively analyzed. RESULTS:Twenty-one case reports were included. Most patients were female (76.2%), with a mean age of 61 years. Neurological manifestations predominated, with tremor being the most frequent symptom (61.9%), followed by altered mental status (42.9%), decreased level of consciousness (38.1%), and gait disturbance or ataxia (38.1%). Speech disturbances, myoclonus, and gastrointestinal symptoms (nausea, vomiting, or diarrhea) were also commonly reported. Serum lithium concentrations exceeded 1.5 mmol/L in 81.0% of cases, with most classified as severe intoxication; however, clinically significant toxicity also occurred at therapeutic or near-therapeutic levels. Renal dysfunction was frequent, with elevated serum creatinine reported in approximately two-thirds of patients. Polypharmacy was common, particularly involving antipsychotics, diuretics, and antihypertensive agents. The most frequent lithium dose was 600 mg/day, and prolonged exposure (>10 years) occurred in nearly one-third of cases. CONCLUSION:Unintentional lithium toxicity presents with heterogeneous and predominantly neurological manifestations and may occur despite therapeutic serum lithium concentrations. Comprehensive clinical assessment, including neurological examination, renal function evaluation, and medication review, is essential to ensure safer long-term lithium use.
PURPOSE/BACKGROUND:Pharmacogenomics (PGx), or the use of genetic information to assess drug-gene interactions, is an important step toward precision medicine. It is unclear if clinician use of PGx yields better outcomes for their patients. This study compared the effectiveness of combinatorial PGx-guided plus guideline-informed treatment (PGx+GIT) with guideline-informed treatment (GIT) alone to improve well-being in individuals with major depressive disorder. METHODS/PROCEDURES:Eligible participants (N=201) were randomized to PGx+GIT or GIT alone. PGx was measured with the proprietary GeneSight combinatorial test. PGx+GIT participant clinicians received test results within 2 business days to inform decisions about medication changes. Participants completed the World Health Organization Well-Being Index (WHO-5), Patient Health Questionnaire (PHQ-9), and PROMIS Profile physical functioning and social roles and activity domains every 2 weeks for 2 months and then every 2 months for the remaining 10 months. Monthly medication changes operationalized as necessary clinical adjustments were tracked with the medication recommendation tracking form. FINDINGS/RESULTS:Both groups improved average well-being over the 12-month study period (model-based change in WHO-5 per log (week) [95% CI]: 4.1 [3.3, 5.0] PGx+GIT and 4.8 [4.0, 5.5] GIT). PGx+GIT did not result in superior improvement in well-being (model-based difference [95% CI]: -0.6 [-1.8, 0.5], P =0.270), or any secondary outcomes. The effect of randomized treatment on well-being was not moderated by depression severity, number of previous failed medications for major depressive disorder, or presence of a comorbid condition. IMPLICATIONS/CONCLUSIONS:These data suggest PGx+GIT was not superior to GIT alone, possibly due to a ceiling effect of GIT, or PGx did not yield better results.
PURPOSE:Agitation can occur in patients with schizophrenia, schizoaffective disorder, and bipolar disorder. This study evaluated the efficacy of sublingual dexmedetomidine, a selective alpha-2 adrenergic receptor agonist, for the treatment of acute agitation in "real-world" psychiatric inpatients. METHODS:This was a pragmatic, randomized, open-label, active-controlled study, conducted at Temple University Episcopal Hospital in Philadelphia, PA. Participants were inpatients with a diagnosis of schizophrenia, schizoaffective disorder, or bipolar disorder, and were randomized in a 1:1 manner to receive sublingual dexmedetomidine or oral lorazepam. Participants received sublingual dexmedetomidine 180 mcg (n = 7), sublingual dexmedetomidine 120 mcg (n = 5), or oral lorazepam 2 mg (n = 12) during an episode of agitation. The primary efficacy end point was absolute change from baseline in Positive and Negative Syndrome Scale-Excited Component (PANSS-EC) total score at 2 hours after medication administration. There were no restrictions on concurrent substance use disorders, suicidal ideations, or psychiatric comorbidities. RESULTS:Twenty-four participants self-administered study medication. Diagnoses included schizophrenia 8/24 (33%), schizoaffective disorder 5/24 (21%), and bipolar disorder 11/24 (46%). At 2 hours post-dose, the PANSS-EC total change from baseline was [median (IQR)] -13.0 (-17.0, -10.0) for sublingual dexmedetomidine and -14.0 (-19.0, -12.0) for oral lorazepam. There were no spontaneously reported adverse effects in either group. CONCLUSIONS:At 2 hours post-dose, sublingual dexmedetomidine was effective at reducing acute agitation in "real-world" psychiatric inpatients with schizophrenia, schizoaffective disorder, and bipolar disorder, who may have had psychiatric comorbidities. There were no spontaneously reported adverse effects. The study was not powered to detect differences between treatment groups.
PURPOSE/BACKGROUND:Olanzapine/samidorphan is a combination medication indicated for the treatment of mood and psychotic symptoms with limited weight gain. Samidorphan is a mu-opioid receptor antagonist that is contraindicated in patients actively using opioids. METHODS/PROCEDURES:Retrospective evaluation of olanzapine/samidorphan cases reported to the National Poison Data System between May 1, 2021, and June 30, 2025. We reviewed coded data to identify those possibly describing a patient who experienced opioid withdrawal. Case notes were requested from individual poison centers, and clinical factors were extracted from the notes. FINDINGS/RESULTS:There were 426 cases reported to the National Poison Data System, of which 31 were patients experiencing opioid withdrawal. About half were male, and the median age was 45 years. Buprenorphine and methadone were the most common opioids that patients were previously taking. Opioid withdrawal lasted about 24 hours for most patients. Seven patients were intubated in the course of their withdrawal management. IMPLICATIONS/CONCLUSIONS:Precipitated opioid withdrawal is a known concern when initiating olanzapine/samidorphan in patients using opioids. Withdrawal may last about 24 hours and require inpatient treatment. Careful screening for opioid use may reduce the risk.
Background: Clozapine, an atypical antipsychotic used primarily for treatment-resistant schizophrenia, has been associated with a wide range of side effects, including the rare but serious complication of acute interstitial nephritis (AIN). This systematic review aimed to summarise published cases of clozapine-induced AIN, focusing on clinical presentations, diagnostic findings, treatment approaches, and patient outcomes to improve awareness and management of this adverse reaction. Methods: A systematic search of the databases Medline, Embase, Cochrane Library, and PsycINFO was conducted according to PRISMA guidelines. Two independent reviewers assessed each study for eligibility and study quality, and extracted the data. Results: A total of 13 cases were included in the final analysis. The mean treatment duration of clozapine before AIN onset was 34.8 days. Doses of clozapine ranged from 100 mg to 700 mg daily, with a mean dose of 281.8 mg. Seven cases were noted to be treated concomitantly with sodium valproate. Symptomatology was diverse, and the most common symptom described was fever (8/13 cases). Clozapine was discontinued in all cases. All cases subsequently had resolution of their physical symptoms, and renal function improved in 92% of cases, however one patient developed permanent chronic kidney disease. Other than clozapine cessation, additional treatments utilized included oral corticosteroid therapy, intravenous corticosteroid therapy, and intravenous fluids. Three cases required short-term dialysis therapy. There were no patients requiring long-term dialysis or other renal replacement therapies, and there were no deaths. Conclusions: Clozapine-induced AIN is a rare, idiosyncratic adverse reaction with diverse presentations. Prompt recognition and intervention are essential to prevent long-term renal damage. Routine renal function monitoring during clozapine therapy, akin to agranulocytosis screening, could be considered to facilitate early detection and management of this complication.
Background: 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. Methods: 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. Results: 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. Conclusions: 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.
Background: There are no approved medications to treat methamphetamine use disorder. We conducted a phase 1b, inpatient,randomized, double-blind, placebo-controlled, within-subject crossover study to evaluate the safety of mirtazapine, a potential treatment for methamphetamine use disorder with positive phase 2 trial findings, in people receiving intravenous methamphetamine. Methods: Participants received mirtazapine 30 mg or placebo daily for 5 days, underwent an intravenous methamphetamine 30 mg challenge on day 5, followed by 2 days of washout, and then switched to the other study arm and received a second methamphetamine infusion at day 12. We monitored participants for adverse events, cardiovascular effects, and pharmacokinetics. Results: Participants (N = 15; 12 with no opioid use and 3 on methadone maintenance treatment) reached steady state mirtazapine levels before methamphetamine infusions. During the mirtazapine phase, participants reached methamphetamine peak plasma concentration 0.26 hours earlier than the placebo phase ( P = 0.02); no other impacts on methamphetamine pharmacokinetics were observed. Mirtazapine neither attenuated nor enhanced the expected cardiovascular effects of methamphetamine, including in participants receiving methadone maintenance therapy. Adverse events were similar between mirtazapine 30 mg and placebo. Conclusions: Mirtazapine 30 mg was safe and well-tolerated in people receiving a clinically relevant intravenous methamphetamine challenge, supporting further development of this medication for the treatment of methamphetamine use disorder.
