Ketamine and Esketamine (Spravato) for Depression in Bipolar Disorder: An Introduction - COPE

Ketamine and Esketamine (Spravato) for Depression in Bipolar Disorder: An Introduction

Bipolar depression is one of the conditions for which ketamine is sometimes considered. This article explains what bipolar disorder and bipolar depression are, and discusses the possible role of ketamine in the treatment of bipolar depression.

What is bipolar disorder?

Bipolar disorder is a mood disorder that is characterized by mood highs and mood lows that are more intense and longer lasting than the highs and lows of everyday life. The high phase is called hypomania if mild, and mania, if severe. The low phase is called bipolar depression.

Bipolar depression is characterized by depressed mood that is present for most or all of the day, almost daily; the patient finds it hard to feel better for more than a very brief period even if something pleasant happens. There may be a loss of interest in leisure and pleasure activities, and an excess of negative thoughts and unhappy memories. Thinking and activity may be slowed down. Sleep and appetite are also usually disturbed; there may be too little sleep or too much of sleep, and there may be a loss of appetite and weight or an increase in appetite and weight. Weepiness, and a lack of desire to live may also be present. Some patients may have suicidal urges; a few may attempt and even complete suicide.

How common is bipolar disorder?

There are different types of bipolar disorder, depending on the severity and pattern of occurrence of the high and low phases. A reasonable estimate is that about 2-3% of the population has bipolar disorder that is sufficiently serious to warrant treatment. The condition usually develops in early life and is equally common in men and women.

Treatment of bipolar depression

Bipolar depression, like other kinds of depression, is often treated with antidepressant drugs. However antidepressant drugs are not effective treatments for bipolar depression. Antidepressants can also cause a switch into a hypomania or mania, which is not an acceptable outcome. Antidepressants can also cause roughening of illness, which means that even after recovery, patients spend less time in normal mood and more time in low-intensity phases of disturbed mood. Finally, antidepressants may cause cycle acceleration, which means that highs and lows occur with greater frequency.

Common treatments, including FDA approved medications for bipolar depression, such as lurasidone, quetiapine, and the olanzapine-fluoxetine combination (OFC), although effective, have disadvantages. Quetiapine and OFC are associated with sedation, weight gain and often diabetes mellitus. Lurasidone can cause restlessness and tremor but very little weight gain. Electroconvulsive therapy, which is sometimes viewed as a last resort intervention and is not FDA approved, is very effective in severely ill patients, but can cause memory impairments and requires anesthesia.

Atypical antipsychotics like aripiprazole, olanzapine, risperidone and ziprasidone, as well as mood stabilizers like lamotrigine are commonly used for acute bipolar depression but were found to be non-effective in controlled studies. Their use is discouraged in bipolar depression.

Unfortunately, a lot of patients do not respond well to the usual medications. For example, only about 50-60% of bipolar depression patients improve by at least 50% with the usual drugs, and even fewer become completely well.

Unmet needs

Some patients with bipolar depression may not recover with usual treatments, such as those listed above. Others may be severely ill and suicidal and may need urgent treatment for crisis intervention. Still others may need to recover rapidly to competently attend to ongoing life situations. Ketamine, administered in low doses, may be of unique value in such patients.

Ketamine for bipolar depression

Ketamine has been associated with impressive benefits in bipolar depression. For example, in one study of 53 adults with bipolar depression, a single session of intravenous ketamine resulted in 51% of patients responding and maintaining the response one week later.

Another study was conducted in 16 adults with bipolar depression, all of whom had intense suicidal thoughts. This study detected a substantial reduction in suicidal ideation scores one day after a single session of intravenous ketamine.

A combined analysis of data from 3 randomized controlled trials with a pooled sample size of 69 bipolar depressed patients found that a single session of intravenous ketamine outperformed placebo by a large margin and benefits were evident as early as 40 minutes after the session.

In these studies, ketamine adverse effects were mild and short-lasting. Very importantly, a switch into the high phase ("manic switch") is very rare with ketamine. Thus, the data on the efficacy and tolerability of ketamine in bipolar depression, and in suicidality associated with bipolar depression, supports the findings obtained when ketamine is used to treat patients with major depressive disorder.

Take home message

Intravenous ketamine is a safe and well-tolerated treatment for patients with bipolar depression. Depression scores and suicidal ideation are both reduced rapidly after ketamine infusion.