A combination of olanzapine and samidorphan (OLZ/SAM) is in development for schizophrenia to provide the efficacy of olanzapine while mitigating olanzapine-associated weight gain. The objective of this phase 1 exploratory study was to assess metabolic treatment effects of OLZ/SAM.

Healthy, non-obese adults (18–40 years) were randomized 2:2:1 to once-daily OLZ/SAM, olanzapine, or placebo for 21 days. Assessments included oral glucose tolerance test (OGTT), hyperinsulinemic-euglycemic clamp, weight gain, and adverse event (AE) monitoring. Treatment effects were estimated with analysis of covariance.

Sixty subjects were randomized (OLZ/SAM, n=24; olanzapine, n=24; placebo, n=12); 19 (79.2%), 22 (91.7%), and 11 (91.7%), respectively, completed the study. In the OGTT, olanzapine led to significant hyperinsulinemia (P<0.0001) and significantly reduced insulin sensitivity (2-hour Matsuda index) at day 19 vs baseline (P=0.0012), changes not observed with OLZ/SAM. No significant between-group differences were observed for change from baseline in clamp-derived insulin sensitivity index at day 21. Least squares mean weight change from baseline was similar with OLZ/SAM (3.16 kg) and olanzapine (2.87 kg); both were significantly higher than placebo (0.57 kg; both P<0.01). Caloric intake significantly decreased from baseline to day 22 with OLZ/SAM (P=0.015) but not with olanzapine or placebo. Forty-nine subjects (81.7%) experienced ≥1 AE (OLZ/SAM, 87.5%; olanzapine, 79.2%; placebo, 75.0%).

In this exploratory study, hyperinsulinemia and decreased insulin sensitivity were observed in the OGTT with olanzapine but not with OLZ/SAM or placebo. Clamp-derived insulin sensitivity index and weight changes were similar with OLZ/SAM and olanzapine in healthy subjects during the 3-week study.

This study was funded by Alkermes, Inc.

Lumateperone (ITI-007) is in late-phase clinical development for schizophrenia. Lumateperone has a unique mechanism of action that modulates serotonin, dopamine, and glutamate neurotransmission. This pooled analysis of lumateperone in 3 randomized, double-blind, placebo-controlled studies was conducted to evaluate the safety and tolerability of lumateperone 42mg (ITI-007 60mg).

Data were pooled from the 3 controlled late-phase studies of lumateperone 42mg in patients with acute exacerbation of schizophrenia. Safety assessments of all patients who received at least one dose of any treatment included treatment-emergent adverse events (TEAEs), changes in laboratory parameters, extrapyramidal symptoms (EPS), and vital signs.

The safety population comprised 1,073 patients (placebo [n=412], lumateperone 42mg [n=406], risperidone [n=255]). TEAEs that occurred in the lumateperone 42mg group at a rate of ≥5% and twice placebo were somnolence/sedation (24.1% vs 10.0%) and dry mouth (5.9% vs 2.2%). Rates of discontinuation due to TEAEs with lumateperone 42mg (0.5%) were similar to placebo (0.5%) and lower than risperidone (4.7%). Mean change in weight and rates of EPS-related TEAEs were less for lumateperone 42mg and placebo patients than risperidone patients. Mean change from baseline in metabolic parameters were similar or smaller for lumateperone 42mg vs placebo. Mean changes were notably higher in risperidone patients vs lumateperone 42mg and placebo for glucose, cholesterol, triglycerides, and prolactin.

In this pooled analysis, lumateperone 42mg showed good tolerability with potential benefits over risperidone for metabolic, prolactin, and EPS risks. The only TEAE that occurred in >10% of lumateperone patients was somnolence/sedation, which was impacted by morning administration; in subsequent studies that administered lumateperone in the evening, somnolence/sedation rates were markedly reduced. These results suggest that lumateperone 42mg may be a promising new treatment for schizophrenia.

Supported by funding from Intra-Cellular Therapies, Inc.

Lumateperone (lumateperone tosylate, ITI-007) is an investigational drug for the treatment of schizophrenia, bipolar depression, and other disorders. Lumateperone has a unique mechanism of action that simultaneously modulates serotonin, dopamine, and glutamate neurotransmission. This may provide advantages in the treatment of the broad symptoms associated with schizophrenia, including negative and depression symptoms. In 2 previous placebo-controlled trials in patients with acute schizophrenia, lumateperone 42mg (ITI-007 60mg) demonstrated statistically significant improvement in the Positive and Negative Syndrome Scale (PANSS) Total score compared with placebo. In these studies, lumateperone was well tolerated with a safety profile similar to placebo. This open-label long-term study evaluated the safety and effectiveness of lumateperone 42mg in patients with schizophrenia and stable symptoms.

Patients with stable schizophrenia were treated for up to 1 year with lumateperone 42mg. Safety assessments included adverse events (AEs), body weight, laboratory parameters, and extrapyramidal symptoms (EPS)/motor symptom assessments. Efficacy analyses included evaluation of changes in PANSS Total score and in depression symptoms, as measured by the Calgary Depression Scale for Schizophrenia (CDSS).

In the 1-year open-label study, 602 patients received at least 1 dose of lumateperone 42mg; at the time of this interim analysis, 107 patients had completed 1 year of treatment. Only 4 TEAEs occurred in ≥5% of patients (weight decrease, dry mouth, headache and diarrhea); the majority of AEs were mild or moderate in intensity. Most metabolic parameters and mean prolactin levels decreased from SOC baseline, as did mean body weight and BMI. Based on AE reporting and EPS/motor symptom scales, lumateperone treatment was associated with minimal EPS risk. Lumateperone 42mg treatment was associated with significant reductions in PANSS Total score from baseline, with continuing PANSS improvement throughout the study. In patients with moderate-to-severe depression symptoms at baseline (CDSS>5), mean CDSS scores decreased from 7.4 (baseline) to 3.1 (Day 300); 60% of patients met CDSS response criteria (50% improvement from baseline) by Day 75 and this response rate was maintained through day 300. Similar magnitude of CDSS improvement was seen regardless of concurrent antidepressant therapy.

In long-term treatment, lumateperone was associated with minimal metabolic, EPS, and cardiovascular safety issues relative to current SOC antipsychotic therapy. Lumateperone improved schizophrenia symptoms with continued long-term treatment. In patients with moderate-to-severe depression symptoms at baseline, lumateperone treatment was associated with marked improvement in CDSS scores. These data are consistent with and extend data previously reported in placebo-controlled studies in patients with acute schizophrenia treated with lumateperone.

Supported by funding from Intra-Cellular Therapies, Inc.

False-positives can occur when a medication has a cross-reactivity with the immunoassay, often due to similarity in structure of the parent medication or one of its metabolites to the tested drug. The occurrence of false-positives is mostly affected by the type of immunoassay used and the particular agent being tested. We present a case of a 13 year old female who was status post overdose with lamotrigine with positive urine toxicology with PCP (Phencyclidine.)

Ms. A is a 13 year old female, with significant psychiatric history of Post-Traumatic Stress Disorder and Attention Deficit Hyperactivity Disorder. She denied any psychoactive substances of abuse including PCP. Her history was collaborated by her mother. History revealed that patient was found unresponsive in bed with a suicide note and bottles at her bedside with 13 of 100mg pills of lamotrigine missing and 13 of 50mg pills sertraline. She was brought to pediatric emergency room by ambulance activated by her mother. On arrival to the hospital, the patient was not verbally responsive; she was responsive only to tactile stimuli. Her vital signs were within normal limits. Her urine toxicology was positive for PCP. Her Basic Metabolic Panel, Liver Function Test, and Complete Blood Count were within normal. She was stabilized after two days and was transferred to child and adolescent psychiatry unit for continued treatment. She was treated with Zoloft 100mg daily, Seroquel 150mg daily, and Valproic Acid of 750mg po total daily dose (blood level 68.1 μg/mL) with good effects on her impulse control and mood lability.

The literature describes that lamotrigine can cause false positive urine toxicology for PCP. In Our case report, our patient denied any history of substance abuse and it was known that she overdosed on lamotrigine. Although a repeat urine toxicology was not done because of patient refusal to cooperate at that time, the suspicion that the positive urine toxicology for PCP was most likely from medication cross reactivity in a patient who has no clinical history of PCP use.

Eye’ve Seen Enough: Oculogyric Crisis in a 13 year old Male Treated for Comorbid ADHD and Psychosis After Stopping Lisdexamphetamine

Oculogyric crisis is a dystonic movement disorder caused by sustained contractions of ocular muscles that may last minutes to hours. It is known to occur during hypodopaminergic states. Combined use of stimulants and antipsychotics increase the risk for developing a hypodopaminergic state in the brain leading to various dystonic reactions described as a stimulant-antipsychotic syndrome (SAS).

A unique example of SAS occurred in a 13 year-old male with comorbid ADHD and schizoaffective disorder hospitalized for acute psychotic decompensation who had been treated for several months with risperidone and lisdexamphetamine. On admission, the patient had received olanzapine 5mg ODT for acute agitation and lisdexamphetamine was discontinued. He started to cross-taper from risperidone to quetiapine. In this setting he developed dystonia including an oculogyric crisis that resolved with diphenhydramine.

In this case the use of lisdexamphetamine and risperidone may have set up an environment where there was decreased endogenously made dopamine and up-regulation of postsynaptic dopamine receptors. Upon discontinuation of the lisdexamphetamine and acute use of additional atypical antipsychotics (olanzapine and quetiapine), the body experienced a hypodopaminergic state resulting in dystonic reactions that included an oculogyric crisis. This case is unique from previously reported cases by occurring with the use and discontinuation of lisdexamphetamine while most reported cases involved a derivative of methylphenidate as the stimulant. This report adds to the literature showing the importance of monitoring and being aware of potential medication interactions especially when treating for comorbid conditions. This is even more important to recognize after adding or removing either of these medications.

Funding: no funding.