Rapid Antidepressant Effects of Ketamine in Major Depression

This study examines whether Ketamine can cause a rapid-next day antidepressant effect in patients with Major Depression/Bipolar Disorder .

Purpose: This study will test whether a single dose of ketamine - a drug that blocks a brain receptor called NMDA - can cause a rapid (next day) antidepressant effect in patients with major depression. Several medications are effective for treating depression; however, they take weeks or months to achieve their full effects. A more rapidly acting antidepressant would have a significant impact on the treatment of depression. In a previous study, ketamine produced a rapid antidepressant effect within hours, but the effect lasted less than 1 week. Understanding how ketamine works may lead to a better understanding of the causes of depression and the design of a longer lasting rapidly acting antidepressant.Patients between 18 and 65 years of age who are currently experiencing an episode of major depression of at least 4 weeks duration and have not responded to two treatment trials may be eligible for this study. Candidates are screened with a medical and psychiatric history, physical examination, and blood and urine tests.Participants undergo the following tests and procedures:Medication tapering: Patients who are taking medications for depression are tapered off the drugs over a 1- to 2-week period. Ketamine/placebo trial: Patients are given a single dose of either ketamine or placebo (an inactive substance), administered intravenously (through a vein) over 40 minutes. After 7 days, patients are given another dose of study drug in crossover fashion; that is, those who previously took ketamine are switched to receive placebo, and those who took placebo are switched to ketamine. Oximetry (measurement of blood oxygen), pulse, and blood pressure are measured continuously for 1 hour before and 4 hours after each ketamine or placebo dose to monitor safety. Interviews and rating scales: Patients complete a series of psychiatric rating scales to assess the effects of the study drug on mood and thinking. The rating scales are repeated up to 18 times during the study, with each time taking about 15 to 20 minutes. Physical examination and laboratory tests: Patients have a physical examination, blood tests, weight measure, and electrocardiogram (ECG) at the beginning and end of the study.

Bipolar affective disorder (manic-depressive illness) and unipolar depression are common,

severe, chronic and often life-threatening illnesses. Impairment in physical and social functioning resulting from depression can be just as severe as other chronic medical illnesses. Recent preclinical and clinical studies suggest that the glutamatergic system is involved in the mechanism of action of antidepressants. In two separate trials, we tested riluzole (an inhibitor of glutamate release) and found it to have antidepressant properties in patients with unipolar and bipolar depression (Zarate et al. 2004, 2005). In another study, we found that the non-competitive NMDA antagonist (ketamine) was effective in treatment-resistant major depression. Ketamine resulted in rapid, robust and relatively sustained antidepressant effects. Response with ketamine occurred within 2 hours and last approximately 1 week (Zarate et al in 2006). The current protocol consists of 6 studies designed to address 6 major questions. Two of these studies (1 and 5) have met their enrollment quota and sufficient analyzable data has been obtained.

Study 1 (Rapid improvement research in unipolar depression)

Does the NMDA antagonist ketamine produce rapid antidepressant effects in patients with treatment-resistant major depression? Patients, ages 18 to 65 years with treatment-resistant major (unipolar) depression will in a double-blind crossover study receive either intravenous ketamine or saline solution (Study completed).

Study 2 (Rapid improvement research in bipolar depression)

Does the NMDA antagonist ketamine produce rapid antidepressant effects in patients with treatment-resistant bipolar depression? Patients, ages 18 to 65 years with treatment-resistant

bipolar depression will in a double-blind crossover study receive either intravenous ketamine or saline solution added to a mood stabilizer (lithium or valproate).

Study 3 (Rapid and sustained improvement research in unipolar depression)

Does riluzole (an inhibitor of glutamate release) prevent relapse in patients with treatment-resistant major depression who have rapidly responded to a single intravenous dose of ketamine? Patients, ages 18 to 65 years, with treatment-resistant major (unipolar) depression who have rapidly responded to a single intravenous dose of ketamine will in a double-blind study receive either riluzole or placebo to determine if the rapid response obtained can be sustained.

Substudy 4 (Predictors and neural correlates of antidepressant response to ketamine)

What are the predictors and neural correlates of antidepressant response to ketamine? Patients, ages 18 to 65 years with treatment-resistant MDD and BD will, in a double-blind crossover study, receive either intravenous ketamine or saline solution and multimodal MRI, MEG and polysomnography.

Our primary hypotheses for these studies are: 1) rapid response (same or next day) can be

achieved in patients with treatment-resistant major (unipolar) depression, 2) rapid response (same or next day) can be achieved in patients with treatment-resistant bipolar depression, 3) rapid response (same or next day) can be sustained in patients with treatment-resistant unipolar depression, and 4) predictors and neural correlates of antidepressant response to ketamine can be identified.

Substudy 5 (Neurophysiological Mechanisms of Rapid Antidepressant Response to Ketamine)

Will activity of glutamatergic circuits within the brain change following the onset of ketamine-induced antidepressant effects help predict response to ketamine? Drug-free bipolar and unipolar patients participating in Substudies 2 and 3 will undergo PET scans before and 2-hours following drug infusion (consistent with the timing of onset of antidepressant effects). (Study completed)

Substudy 6 (Role of Glutamatergic and GABAergic systems in treatment response to ketamine/riluzole)

Will subjects with treatment-resistant major depression who receive ketamine followed by riluzole show a greater increase in the concentration of GABA, glutamate, glutamine and NAA compared to subjects randomized to placebo? Unipolar patients participating in Substudy 3 will have 1H-MRS scans immediately before both infusions (ketamine, placebo) and at the end of each experimental phase.

• Depression
• Major Depression/Bipolar Disorder

• Drug: Ketamine
  N/A
• Drug: Riluzole
  N/A
• Drug: FDG
  Radiotracer

• Agnoli A, Ruggieri S, Casacchia M. Restatement and prospectives of ergot alkaloids in clinical neurology and psychiatry. Pharmacology. 1978;16 Suppl 1:174-88.
• Agren H, Mefford IN, Rudorfer MV, Linnoila M, Potter WZ. Interacting neurotransmitter systems. A non-experimental approach to the 5HIAA-HVA correlation in human CSF. J Psychiatr Res. 1986;20(3):175-93.
• Anderson IM. SSRIS versus tricyclic antidepressants in depressed inpatients: a meta-analysis of efficacy and tolerability. Depress Anxiety. 1998;7 Suppl 1:11-7.
• Ionescu DF, Luckenbaugh DA, Niciu MJ, Richards EM, Slonena EE, Vande Voort JL, Brutsche NE, Zarate CA Jr. Effect of baseline anxious depression on initial and sustained antidepressant response to ketamine. J Clin Psychiatry. 2014 Sep;75(9):e932-8. doi: 10.4088/JCP.14m09049.
• Ballard ED, Ionescu DF, Vande Voort JL, Niciu MJ, Richards EM, Luckenbaugh DA, Brutsché NE, Ameli R, Furey ML, Zarate CA Jr. Improvement in suicidal ideation after ketamine infusion: relationship to reductions in depression and anxiety. J Psychiatr Res. 2014 Nov;58:161-6. doi: 10.1016/j.jpsychires.2014.07.027. Epub 2014 Aug 12.
• Cornwell BR, Salvadore G, Furey M, Marquardt CA, Brutsche NE, Grillon C, Zarate CA Jr. Synaptic potentiation is critical for rapid antidepressant response to ketamine in treatment-resistant major depression. Biol Psychiatry. 2012 Oct 1;72(7):555-61. doi: 10.1016/j.biopsych.2012.03.029. Epub 2012 Apr 21.
• Zarate CA Jr, Brutsche NE, Ibrahim L, Franco-Chaves J, Diazgranados N, Cravchik A, Selter J, Marquardt CA, Liberty V, Luckenbaugh DA. Replication of ketamine's antidepressant efficacy in bipolar depression: a randomized controlled add-on trial. Biol Psychiatry. 2012 Jun 1;71(11):939-46. doi: 10.1016/j.biopsych.2011.12.010. Epub 2012 Jan 31.
• Diazgranados N, Ibrahim L, Brutsche NE, Newberg A, Kronstein P, Khalife S, Kammerer WA, Quezado Z, Luckenbaugh DA, Salvadore G, Machado-Vieira R, Manji HK, Zarate CA Jr. A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry. 2010 Aug;67(8):793-802. doi: 10.1001/archgenpsychiatry.2010.90.
• DiazGranados N, Ibrahim LA, Brutsche NE, Ameli R, Henter ID, Luckenbaugh DA, Machado-Vieira R, Zarate CA Jr. Rapid resolution of suicidal ideation after a single infusion of an N-methyl-D-aspartate antagonist in patients with treatment-resistant major depressive disorder. J Clin Psychiatry. 2010 Dec;71(12):1605-11. doi: 10.4088/JCP.09m05327blu. Epub 2010 Jul 13.
• Machado-Vieira R, Yuan P, Brutsche N, DiazGranados N, Luckenbaugh D, Manji HK, Zarate CA Jr. Brain-derived neurotrophic factor and initial antidepressant response to an N-methyl-D-aspartate antagonist. J Clin Psychiatry. 2009 Dec;70(12):1662-6. doi: 10.4088/JCP.08m04659. Epub 2009 Sep 8.
• Phelps LE, Brutsche N, Moral JR, Luckenbaugh DA, Manji HK, Zarate CA Jr. Family history of alcohol dependence and initial antidepressant response to an N-methyl-D-aspartate antagonist. Biol Psychiatry. 2009 Jan 15;65(2):181-4. doi: 10.1016/j.biopsych.2008.09.029. Epub 2008 Nov 8.
• Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, Charney DS, Manji HK. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006 Aug;63(8):856-64.

• STUDY POPULATION (FOR SUBSTUDY 4)

Male and female patients, ages 18 to 65 years with a diagnosis of MDD, currently depressed or in a current major depressive episode of BD without psychotic features will be recruited into this substudy. In addition, healthy volunteers will also be recruited into this substudy.

The proportion of ethnic minorities (vs. Caucasian) in the total sample will be consistent with the ethnic/racial proportions of the Washington D.C. and Montgomery county areas. We appreciate that minority groups tend to be underrepresented in research samples for mood disorders. Therefore, we make every effort to recruit minority patients, in order to ensure that the subject sample represents the community. Although it is not known whether racial differences will affect responses to pharmacotherapy, Substudy 4 will assess such effects; however, the size of the racial subsamples may be too small to identify statistically meaningful differences.

INCLUSION CRITERIA FOR PATIENTS WITH MDD OR BD:

Male or female subjects, 18 to 65 years of age.

Age of onset less than 40 years of age.

Female subjects of childbearing age must be using a medically accepted method of contraception.

Each subject must have a level of understanding sufficient to agree to all required tests and examinations and sign an informed consent document.

Subjects must fulfill DSM-IV criteria for Major Depression single episode or recurrent without psychotic features, or Bipolar Disorder (296.5 for Bipolar I Disorder or 296.89 for Bipolar II Disorder) without psychotic symptoms based on clinical assessment and confirmed by a structured diagnostic interview (SCID-P).

Subjects must have an initial score on the MADRS of at least 20 at screening, and at baseline for Phase I of Substudy 4.

Current or past history of lack of response to one adequate antidepressant trial, operationally defined using the Antidepressant Treatment History Form (ATHF); a failed adequate trial of ECT would count as an adequate antidepressant trial.

Current major depressive episode of at least 4 weeks duration.

In women of childbearing age, a negative pregnancy test within 24 hours of MRI.

EXCLUSION CRITERIA FOR PATIENTS WITH MDD OR BD:

Current psychotic features or a diagnosis of Schizophrenia or any other psychotic disorder as defined in the DSM-IV.

Subjects with a history of DSM-IV drug or alcohol dependency or abuse (except for caffeine or nicotine dependence) within the preceding 3 months. In addition, subjects who currently are using drugs (except for caffeine or nicotine) must not have used illicit substances in the 2 weeks prior to screen and must have a negative alcohol and drug urine test (except for prescribed benzodiazepines) urine test at screening.

Female subjects who are either pregnant or nursing.

Serious, unstable illnesses including hepatic, renal, gastroenterologic, respiratory, cardiovascular (including ischemic heart disease), endocrinologic, neurologic, immunologic, or hematologic disease.

Presence of any medical illness likely to alter brain morphology and/or physiology (e.g., hypertension, diabetes) even if controlled by medications.

Clinically significant abnormal laboratory tests.

Subjects with clinical hypothyroidism or hyperthyroidism.

Subjects with one or more seizures without a clear and resolved etiology.

Treatment with a reversible MAOI within two weeks prior to Phase I of Substudy 4.

Treatment with fluoxetine within five weeks or aripiprazole within three weeks before Phase I of Substudy 4.

Treatment with any other concomitant medication (Appendix 3) 14 days prior to Phase I of Substudy 4.

Presence of metallic (ferromagnetic) implants (e.g, heart pacemaker, aneurysm clip).

Subjects who, in the investigator s judgment, pose a current serious suicidal or homicidal risk, or who have a MADRS item 10 score of > 4.

No structured psychotherapy will be permitted during Substudy 4.

INCLUSION CRITERIA FOR HEALTHY CONTROL SUBJECTS:

Age 18-65 years.

Written informed consent completed.

In women of childbearing age, a negative pregnancy test within 24 hours of MRI.

EXCLUSION CRITERIA FOR HEALTHY CONTROL SUBJECTS:

Current or past Axis I diagnosis

Presence of metallic (ferromagnetic) implants (e.g., heart pacemaker, aneurysm clips).

Presence of medical illness likely to alter brain morphology and/or physiology (e.g., hypertension, diabetes) even if controlled by medications.

Treatment with any of the exclusionary medications detailed in Appendix 3 14 days prior to Phase 1 of the Substudy 4.

Current or past alcohol or substance abuse or dependence diagnosis (except for nicotine or caffeine).

Presence of psychiatric disorders in first-degree relatives.