• Social Anxiety Disorder (SAD) is common and causes significant impairment.
• First-line treatments for Social Anxiety Disorder are only partially effective. Many SAD patients experience little or inadequate symptom relief with available treatments.
• Ketamine is a potent NMDA receptor antagonist. Ketamine represents an agent with a potentially novel mechanism of action for the treatment of anxiety disorders.
• Ketamine has demonstrated efficacy in the treatment of psychiatric disorders closely related to Social Anxiety Disorder including Major Depression, Bipolar Depression and possibly Obsessive-Compulsive Disorder.

Ketamine represents the possibility to provide rapid symptom relief to patients with SAD and may provide the mechanism for future drug development to treat SAD more rapidly and effectively.

Roughly one-third to one-half of patients with generalized SAD do not experience significant clinical benefit from current evidence-based treatment for SAD such as pharmacotherapy with selective serotonin reuptake inhibitors (SSRI) or venlafaxine and cognitive behavioral therapy (CBT). Failure of anxiety relief in patients with SAD is a source of substantial morbidity, distress, and decreases in quality of life. Novel pharmacological treatments are needed to improve patient outcomes with SAD.

Converging lines of evidence from neuroimaging and pharmacological studies support the importance of glutamate abnormalities in the pathogenesis of SAD. In a Magnetic Resonance Spectroscopy (MRS) study, an elevated glutamate to creatinine ratio was found in the anterior cingulate cortex of SAD patients when compared to healthy controls. Elevated thalamic glutamine levels have been demonstrated in patients with SAD. Pre-clinical rodent studies have also established a strong link between glutamate regulation and anxiety.

Ketamine is a potent antagonist of the N-methyl-D-aspartate (NMDA) receptor, a major type of glutamate receptor in the brain. Ketamine is routinely used for anesthetic induction because of its dissociative properties. However in research studies, ketamine is effective treatment in reducing symptoms in depressive and possibly anxiety disorders. In multiple controlled clinical studies, ketamine has produced a rapid antidepressant effect in unipolar and bipolar depression. Ketamine's anti-depressant effects peak 1-3 days following infusion. Ketamine's antidepressant effect is observed long after ketamine has been metabolized and excreted by the body and after ketamine's sedative and dissociative effects have dissipated.

The results of several clinical studies suggest that ketamine may also have significant anxiolytic effects. Patients with major depressive disorder given a single ketamine infusion have shown strong and significant reductions in comorbid anxiety symptoms. A trial including 11 depressed patients demonstrated a significant reduction in anxiety symptoms (Hamilton Anxiety Rating Scale (HAM-A)) following ketamine infusion. This improvement is supported by one of the earlier placebo-controlled trials of ketamine which demonstrated that the psychic anxiety item was one of 4 (out of 21) items on the Hamilton Depression Rating Scale (HAM-D) demonstrating significant improvement after ketamine infusion.

The investigators goal is to conduct a randomized, placebo-controlled crossover study to explore the efficacy and time course of action of intravenous ketamine in the treatment of SAD.

Inclusion Criteria:

1. Adult between the ages of 18 and 65 years
2. Meet DSM IV criteria for Social Anxiety Disorder by structured clinical interview (SCID) and have a LSAS >60 with or without co-morbid MDD

Exclusion Criteria:

1. Positive pregnancy test
2. History of substance abuse disorder within the last 6 months or positive urine toxicology on screening (within the previous 6 months).
3. History of pervasive developmental disorder or psychotic disorder by DSM-IV-TR criteria
4. Medical comorbidity that significantly increases the risks associated with ketamine infusion (e.g. untreated hypertension, significant cardiovascular disease)

1 hour after infusion

The Clinician-Administered Dissociative State Scale (CADSS) is a 27-item scale. The subjective component consists of 19 clinician administered items that are meant to depict the subjects state at the time that the items are being asked of them. The range of possible responses: 0 = not at all, 1 = slightly, 2= moderately, 3 = considerably, 4 = extremely. The clinician rates the 8 subjective items.

A significant limitation of our study was that 17 of 18 subjects correctly identified when they received ketamine, suggesting that the use of saline as a placebo control for ketamine led to inadequate blinding.