A single infusion of ketamine improves depression scores in patients with anxious bipolar depression.

Patients with both bipolar disorder and comorbid anxiety disorders/anxiety symptoms have worse clinical outcomes compared to non-anxious bipolar disorder (1, 2). This anxious subtype of bipolar disorder is common, with a prevalence of approximately 25–50% in some studies (3, 4). Furthermore, anxiety’s influence in bipolar disorder is becoming increasingly recognized, as reflected by the addition of an anxious distress specifier to the diagnosis of bipolar disorder in the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) (1). Regarding patients with primary bipolar illness accompanied by symptoms of anxiety, one study examined a sample of patients with bipolar disorder (type I and II) and found that high anxiety symptoms (≥ 16 on anxiety items from the Schedule for Affective Disorders-Lifetime version) were significantly associated with alcohol abuse, cyclothymia, and more suicide attempts (4)—all factors that increase morbidity. Also in this sample, high anxiety within bipolar disorder predicted a trend toward non-responsiveness to lithium. Similarly, another study found non-remission in bipolar disorder to be associated with current or past anxiety symptoms, as well as a history of panic attacks, more severe depression, and a greater number of past depressive or manic episodes (3). Patients with bipolar disorder with anxiety report significantly more side effects despite no difference in blood lithium levels or dosing compared to patients without anxiety, and require a larger number of medication trials in order to achieve remission, primarily due to the need for more antidepressant trials (3). Regarding randomized controlled trials (RCTs), risperidone monotherapy was not an effective anxiolytic in patients with bipolar disorder with anxious symptoms and comorbid panic disorder or generalized anxiety disorder (GAD) (5). Similarly, ziprasidone monotherapy did not significantly improve anxiety symptoms in patients with bipolar disorder with comorbid panic disorder or GAD; instead, it was associated with more negative side effects versus placebo (6). Despite the clinical challenge that anxious bipolar depression presents, some positive findings exist in the literature. A review of 11 RCTs found that quetiapine (monotherapy or in combination) was associated with significant improvements in anxiety [measured by the Hamilton Anxiety Rating Scale (HAM-A)] in bipolar depression (7). Similarly, patients with bipolar depression and high anxiety (≥ 18 on the HAM-A) experienced significant reductions in symptoms of both depression and anxiety following treatment with olanzapine or olanzapine-fluoxetine combination versus placebo; however, weight gain and increased cholesterol levels were also significant (8). Recently, lurasidone monotherapy (9) and in combination with lithium or valproate (10) was found to significantly reduce anxiety symptoms in patients with bipolar depression. Despite a few positive studies, anxious bipolar disorder is generally a more severe subtype that is clinically challenging to treat, especially during a depressive episode. Although of urgent clinical need, novel psychopharmacological interventions for anxious bipolar depression have been understudied (11). Ketamine is of particular interest for difficult-to-treat patients with depression because it differs from many currently available antidepressants in that it is an N-methyl-D-aspartate (NMDA) receptor antagonist, though it’s precise mechanism of antidepressant action remains largely unknown. A single intravenous infusion of ketamine (0.5 mg/kg over 40 minutes) has been shown to have a rapid (within 40 minutes) and robust antidepressant effect when given to moderately-to-severely depressed patients with bipolar disorder (despite having failed multiple medications trials) maintained on therapeutic levels of lithium or valproate; this effect lasted through Day 3 post-infusion (12, 13). In addition, ketamine rapidly improved suicidal ideation in these patients (12). Indeed, ketamine has been shown to rapidly and robustly reduce symptoms of depression in a sample of patients with treatment-resistant bipolar disorder (with and without anxiety) (13, 14). What remains unknown is whether stratifying patients with bipolar depression based on baseline anxious status predicts a poorer treatment response to ketamine, since anxiety generally predicts poorer outcome for standard treatments for bipolar disorder (3, 4). We sought to determine whether baseline anxiety status reduced ketamine’s ability to effectively treat depression. In order to answer this question, we examined ketamine’s effect on depression scores over 14 days post-infusion in patients with both anxious and non-anxious bipolar depression.