Lamotrigine

This was a double-blind, placebo-controlled study of the acute efficacy of IV ketamine or placebo added to ongoing antidepressant therapy (ADT) in the treatment of major depressive disorder (MDD) adults with TRD. Following a washout period for patients on prohibited psychotropic agents, 99 eligible subjects were randomly assigned to one of five 40-minute infusion arms in a 1:1:1:1:1 fashion: a single dose of ketamine 0.1 mg/kg (n=18), a single dose of ketamine 0.2 mg/kg (n=20), a single dose of ketamine 0.5 mg/kg (n=22), a single dose of ketamine 1.0 mg/kg (n=20), and a single dose of midazolam 0.045 mg/kg (active placebo) (n=19) (see Figure 1), to minimize the unblinding risk due to AEs, as in Murrough et al^{16 (link)}. Prior to randomization, patients were grouped by BMI (Group I: BMI ≤30; Group II: BMI >30), and were block randomized into each arm of the study, with the mg/Kg ratio being maintained across all BMIs. The primary endpoint assessments were carried out over 3 days and all subjects were followed for 30 days to examine the benefit durability (see Figure 1).
The study assessments were performed at Days 0, 1, 3, 5, 7, 14, and 30 to assess the safety and efficacy of all doses of ketamine compared to active placebo therapy in depressed patients demonstrating an inadequate response to at least 2 adequate ADTs during the current major depressive episode (TRD). This report focuses on the outcome during the acute phase of the study (Days 0 through 3). This trial was conducted across six U.S. academic sites (Massachusetts General Hospital, Baylor College of Medicine/Michael E. Debakey VA Medical Center, Icahn School of Medicine at Mount Sinai, Stanford University School of Medicine, University of Texas Southwestern, and Yale University), according to the U.S. FDA guidelines and Declaration of Helsinki. IRB- and NIMH DSMB-approved written informed consent was obtained from all patients.
All enrolled subjects were male and female outpatients between the ages of 18–70 years old with a diagnosis of MDD in a current depressive episode of at least eight week-duration (as defined by the DSM-IV-TR™). The diagnosis of MDD was supported by the Structured Clinical Interview for DSM-IV (SCID-I/P). Furthermore, all subjects had TRD, defined as failure to achieve a subjective satisfactory response (e.g., less than 50% improvement of depression symptoms) to at least two adequate treatment courses during the current depressive episode (including the current ADT). All study participants with MDD were required to be on a stable (for at least 4 weeks) and adequate (according to the MGH Antidepressant Treatment Response Questionnaire or ATRQ) dose of ongoing ADT, with a total treatment duration of at least 8 weeks. Concurrent hypnotic therapy was allowed if the therapy had been stable for at least 4 weeks prior to screening and was expected to remain stable during the study. Patients were also allowed to continue treatment with benzodiazepines used for anxiety if therapy had been stable for at least 4 weeks prior to screening and expected to remain stable during the study. Patients on exclusionary concomitant psychotropic medications (e.g., opioids, tramadol, valproic acid, lamotrigine, carbamazepine, barbiturates, eszopiclone, stimulants, NMDA receptor antagonists such as memantine), were included only if they had been free of the exclusionary medication post-taper for five half-lives within the maximum screening period (28 days). Furthermore, subjects could be in concurrent psychotherapy, if stable. All subjects had a Montgomery Asberg Depression Rating Scale^{17 (link)} (MADRS) score ≥20 at both the screen and baseline visits. All included patients were required to have a BMI between 18–35 kg/m².
Major exclusion criteria were as follows: Failure to achieve satisfactory response (e.g., less than 50% improvement of depression symptoms) to >7 treatment courses of a therapeutic dose of an ADT of at least 8 weeks duration in the current major depressive episode, MADRS total score <20 at screening or baseline; a primary Axis I disorder other than MDD; current substance use disorder (abuse or dependence), with the exception of nicotine dependence, within 6 months prior to screening; and any history of ketamine or PCP drug use. All subjects underwent urine drug testing at screening. Other major exclusion criteria included a history of bipolar disorder, schizophrenia or schizoaffective disorders, or any history of psychotic symptoms in the current or previous depressive episodes. Furthermore, previous participants in research studies involving glutamatergic agents for depression were also excluded.
Following the in-person screen, the diagnosis and adequacy of treatment was confirmed by remote, independent raters from the Massachusetts General Hospital (MGH) Clinical Trials Network and Institute (CTNI), via a teleconference administration of the Mood Disorders module of the SCID-I/P, MADRS, and the MGH ATRQ.