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Ketamine, a drug introduced in the 1960s as an anesthetic agent and still used for that purpose, has garnered marked interest over the past two decades as an emerging treatment for major depressive disorder. With increasing evidence of its efficacy in treatment-resistant depression and its potential anti-suicidal action, a great deal of investigation has been conducted on elucidating ketamine’s effects on the brain. Of particular interest and therapeutic potential is the ability of ketamine to exert rapid antidepressant properties as early as several hours after administration. This is in stark contrast to the delayed effects observed with traditional antidepressants, often requiring several weeks of therapy for a clinical response. Furthermore, ketamine appears to have a unique mechanism of action involving glutamate modulation via actions at the N-methyl-D-aspartate (NMDA) and [Formula: see text]-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, as well as downstream activation of brain-derived neurotrophic factor (BDNF) and mechanistic target of rapamycin (mTOR) signaling pathways to potentiate synaptic plasticity. This paper provides a brief overview of ketamine with regard to pharmacology/pharmacokinetics, toxicology, the current state of clinical trials on depression, postulated antidepressant mechanisms and potential biomarkers (biochemical, inflammatory, metabolic, neuroimaging sleep-related and cognitive) for predicting response to and/or monitoring of therapeutic outcome with ketamine.

We investigated the prevalence of anxiety disorders in a sample of individuals with chronic schizophrenia, controlling for anxiety symptoms that may be related to delusions and hallucinations, and the possible differences in clinical variables between the groups. Individuals with a diagnosis of schizophrenia and able to give informed consent were recruited from the community. The Mini International Neuropsychiatric Interview (MINI) was administered to both confirm the DSM-IV diagnosis of schizophrenia and screen for comorbid anxiety disorders. If a comorbid anxiety disorder was found, its relation to the individual's delusions and hallucinations was examined. Clinical rating scales for schizophrenia were administered as well as rating scales for specific anxiety disorders where appropriate. Overall, anxiety disorders ranged from 0% [ for Post Traumatic Stress Disorder (PTSD)] to 26.7% [ for generalized anxiety disorder (GAD) and agoraphobia without panic] with lower rates when controlled for anxiety symptoms related to delusions and hallucinations. In investigating clinical variables, the cohort was initially divided into schizophrenics with no anxiety disorders and those with an anxiety disorder; with further analyses including schizophrenics with anxiety disorders related to delusions and hallucinations and those with anxiety disorders not related to delusions and hallucinations. The most consistent difference between all the groups was on the PANSS-G subscale. No significant differences were found on the remaining clinical variables. Comorbid anxiety disorders in schizophrenia can be related to the individual's delusions and hallucinations, though anxiety disorders can occur exclusive of these positive symptoms. Clinicians must be aware that this comorbidity exists in order to optimize an individual's treatment.

Objective: Patients with major depressive disorder often have limited response to first-line and second-line medications; hence, novel pharmacological treatments are needed for treatment-resistant depression (TRD). Ketamine, an N-methyl-d-aspartate (NMDA) receptor antagonist, has demonstrated rapid antidepressant effects in patients with TRD. The Canadian Network for Mood and Anxiety Treatments (CANMAT) convened a task force to review the evidence for efficacy and safety of racemic ketamine and to provide recommendations for its use in clinical practice. Methods: A systematic review was conducted with computerized search of electronic databases up to January 31, 2020 using combinations of search terms, inspection of bibliographies, and review of other ketamine guidelines and consensus statements. The level of evidence and lines of treatment were assigned according to CANMAT criteria. Recommendations were given in question–answer format. Results: Intravenous (IV) racemic ketamine given as a single infusion has Level 1 evidence for efficacy in adults with TRD. The evidence for multiple infusions, given as an acute series or as ongoing maintenance treatment, is limited to Level 3. Adverse events associated with ketamine infusions include behavioral (e.g., dissociative symptoms) and physiological (e.g., hypertension) events. There is only Level 3 or 4 evidence for non-IV formulations of racemic ketamine. Consensus recommendations are given for clinical administration of IV ketamine including patient selection, facility and personnel issues, monitoring, and maintaining response. Conclusions: Single-dose IV racemic ketamine is a third-line recommendation for adults with TRD. The need for repeated and maintenance ketamine infusions should be carefully assessed on a case-by-case basis with consideration of potential risks and benefits. Because of limited evidence for efficacy and risk for misuse and diversion, the use of oral and other formulations of racemic ketamine should be limited to specialists with ketamine-prescribing expertise and affiliations with tertiary or specialized centers.

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Maintenance ketamine treatments may be an effective way of maintaining treatment response in some ketamine responders. Future research is required to determine optimal length of treatment in those who respond to ketamine and to track adverse effects over a longer time.