Role of Ketamine in Depression

Role of Ketamine
in Depression

Overview and Summary

Depression is the single most important indication for the use of ketamine in psychiatry.

Response and remission

Response means that depression improves by at least 50%. Remission means that depression has lifted completely or near-completely.

Antidepressant drugs take 4-8 weeks to produce response and remission from depression. In sharp contrast to antidepressant drugs, ketamine produces response and even remission in as short a period as 1-2 days. That is, the benefits are dramatic.

Depression is considered to be treatment-resistant if the patient has received 2 or more oral antidepressant drugs without benefit. Ketamine treatment results in dramatic benefits in treatment-resistant major depression, as well. The first study that demonstrated this was published in the year 2006. This study also administered ketamine intravenously.

Subsequently, dozens of studies have shown that ketamine is effective in treating patients with major depression, including treatment-resistant major depression. In almost all of these studies, ketamine was administered intravenously.

The research base demonstrating the efficacy of ketamine comprises randomized controlled trials and meta-analyses.

Randomized controlled trials are studies where patients are randomly allocated to receive either the experimental treatment or a comparison treatment. Such studies are considered to be the gold standard in research.

Meta-analyses are studies in which data from many previous studies, such as randomized controlled trials, are pooled to provide a sort of ‘average’ result. Meta-analyses provide a broader perspective than individual studies.

Randomized controlled trials and meta-analyses have also demonstrated that ketamine rapidly reduces suicidal thoughts and behavior in patients with major depression. This is important because it means that treating suicidal patients with ketamine can save lives.

Current status of ketamine as a treatment for depression

Ketamine is actually a 1:1 mixture of two drugs that have the same chemical formula but a (slightly) different molecular structure.

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The 1:1 mixture is called racemic ketamine, or just ketamine.

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The racemic mixture contains R-ketamine (arketamine) and S-ketamine (esketamine) in equal proportions (1:1).

There are small differences in the way arketamine and esketamine work in the brain.

Racemic ketamine
Esketamine

Most of the studies on the safety and efficacy of ketamine have been conducted on racemic ketamine. These studies include the studies that found ketamine effective as an anesthetic agent, as a treatment for pain, as a treatment for depression, and as a medication that can be used to sedate patients or calm agitated and disturbed patients.

Most of the studies on the safety and efficacy of ketamine in patients with depression (including treatment-resistant depression and depression with suicidality) have been conducted with racemic ketamine administered by the intravenous route.

For patients with depression, racemic ketamine has also been administered by other routes, such as intramuscularly, subcutaneously, sublingually, and orally. However, the intravenous route is the best researched and the best established.

A small but solid body of research has demonstrated the safety and efficacy of esketamine in depressed patients who have failed to respond to one or more previous antidepressant medicines.

Most of the studies on the safety and efficacy of esketamine in patients with depression (including treatment-resistant depression and depression with suicidality) have been conducted with esketamine administered by the intranasal route using a special single-use dispenser.

IS it Effective?

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Is it unipolar depression or bipolar depression?

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Is the patient an adolescent or adult?

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How extensive is the treatment-refractoriness?

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Are there complicating factors, such as presence of catatonic or psychotic symptoms?

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By what route is the ketamine being administered?

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In what dose is the ketamine being administered?

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How many sessions of ketamine treatment will the patient receive?

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Is the patient receiving medications that may interfere with the action of ketamine?

As ball park figures:

More than 50% of depressed patients treated with ketamine can expect at least partial improvement 1-2 days after receiving the treatment.

About a quarter of depressed patients treated with ketamine can expect to experience substantial benefit with the treatment.

Here is a sobering note:

The benefits with ketamine are not lasting. They tend to wear off in 5-7 days. So, ketamine treatment needs to be repeated, and not just once but many times until the depression completely lifts and the patient can be maintained on antidepressant medicines alone. Rarely, patients may need to continue receiving ‘maintenance treatment’ with ketamine for months to years. This is when maintenance treatment with usual antidepressant drugs does not work.

Here is a reassuring note:

The transience of benefit with ketamine is not a limitation of the treatment; it is characteristic of most treatments in medicine. As an example, antidiabetic and antihypertensive medicines are effective for only as long as they are taken. This also applies to other medicines in neuropsychiatry, such as antidepressant and antipsychotic medicines. So, patients who improve with ketamine need to take something else to stay improved. This ‘something else’ can be an antidepressant drug or ketamine, itself.

The many faces of depression and role of Ketamine?

Ketamine is not appropriate for all kinds of depression. Ketamine is used specifically in patients with major depression, and perhaps more specifically in those with major depressive disorder. To understand this, what depression is must first be explained.

There are many different kinds of fever. For example, fever may be due to influenza, typhoid, malaria, or tuberculosis.

Likewise, there are many different kinds of depression. Three examples are provided below.

Depression as an adjustment
reaction to major stress

Failure in an important examination, loss of a large sum of money, loss of job, or living with an alcoholic or chronically ill spouse can stress an individual to the point of depression. In these examples, the depression is an understandable reaction to the stress.

Dysthymia

Some people have poor coping styles and cannot adjust to the stresses and strains of everyday life. They may experience depression and associated symptoms as a consequence. This form of depression is called dysthymia. Dysthymia is different from depression as an adjustment reaction because adjustment reactions result from major stress rather than everyday stress. Most people face the pressures of everyday life without becoming depressed, whereas many may understandably be depressed when faced with major stress.

Major depression

This is a severe form of depression that is usually out of proportion to the stresses that are present, if indeed stresses out of the ordinary are actually present. This form of depression is usually associated with difficulties in coping with the tasks of daily life. This form of depression is usually also associated with biological changes in the body and brain.

Major depression may occur in major depressive disorder or in bipolar disorder. In major depressive disorder, patients experience one or more episodes of depression. In bipolar disorder, patients experience one or more episodes of depression, and also one or more episodes of hypomania or mania. If depressions are conceptualized as ‘low’ phases, hypomania and mania are ‘high’ or ‘hyper’ phases.

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What is explained above is a sim`plification. Detailed diagnostic criteria are available that define different kinds of depression. The diagnoses are made by psychiatrists, who are medical doctors trained in the recognition and treatment of mental health disorders.

Clinically relevant Situations for Use of Ketamine

Ketamine is not used to treat adjustment reactions and dysthytmia. Ketamine is used to treat major depression that occurs either in the context of major depressive disorder or bipolar disorder. The former is sometimes called unipolar depression and the latter, bipolar depression.

In the rest of this section, when ‘depression’ is stated, it should be understood to refer to major depression.

Ketamine has potential for use in the following contexts in patients with major depression:

Depression associated with suicide ideation and risk

Treatment-resistant depression

Severe depression, as an alternative to electroconvulsive therapy (ECT)

Severe, uncomplicated depression

Severe depression, as an alternative to electroconvulsive therapy (ECT)

Let us look at each of these in turn.

1. Depression associated with suicidal ideation and risk

Major depression is often associated with suicidal ideation. Sometimes, the suicidal ideation may be associated with serious risk of self-harm; that is, the patient make plan or actually make a suicide attempt. Sometimes, the self-harm involves head-banging or self-inflicting wounds on the body.

Suicidal ideation is deeply distressing and frightening not only to the patient but also to the caregivers of the patient. Most important of all, suicidal ideation can result in the loss of life. Ketamine is the only treatment that can bring about a dramatic reduction in suicidal ideation along with reduction in the severity of depression.

Much research has demonstrated the efficacy of ketamine in reducing suicidal ideation associated with depression. Thus, ketamine has the potential to be life-saving in patients who are at risk of suicide.

2. Treatment-resistant depression

Depression is considered to be treatment-resistant when the patient fails to respond to at least two trials of antidepressant drugs, belonging to different pharmacological classes, and prescribed in adequate doses for an adequate duration (usually, at lest 4-6 weeks).

Treatment-resistant depression is the most common indication for the use of ketamine in depressed patients. In fact, most of the research on the efficacy of ketamine in depression has been conducted in patients who were treatment-resistant. This is because oral antidepressants are easy to take in the convenience of one’s home. It is only when oral antidepressants do not work that other treatments, such as ketamine, are considered.

3. Severe depression, as an alternative to electroconvulsive therapy (ECT)

ECT is a gold standard treatment for major depression, especially when treatment-resistant, or when accompanied by complications such as suicidal ideation, psychotic symptoms, or catatonia.

Many studies have compared ketamine with ECT. A reasonable conclusion is that, when ECT is administered in its most effective form, that is, as bilateral ECT, ECT is superior to ketamine. However, these studies also show that, in patients who are considered appropriate for ECT, the response and remission rate with ketamine is reasonably good. Furthermore, treatment with ketamine is not associated with cognitive impairment; in contrast, bilateral ECT often produces some degree of memory and other cognitive impairments. So, many experts believe that depressed patients who are referred for ECT could consider trying ketamine first.

In other words, ketamine can be considered as an alternative to ECT in severely depressed patients who are referred for ECT.

4. Severe, uncomplicated depression

Depression is associated with suffering. It is also associated with impaired quality of life, impairments in activities of daily living, and impairment in work performance. This is true even in uncomplicated depression; that is, depression that is not treatment-resistant, nor accompanied by problems such as suicidal ideation, psychotic symptoms, catatonia, or treatment-resistance.

Antidepressant drugs take 4-8 weeks to produce response and remission from depression. Ketamine, in contrast, produces response and even remission in as short a period as 1-2 days. That is, the benefits are dramatic. So, some experts suggest that ketamine can be administered during the early weeks of antidepressant therapy to patients with severe depression even if there are no complications. In such situations, ketamine could help keep the patient moderately well until the antidepressant drug begins to act.

5. Depression with social need for rapid recovery

Antidepressant drugs take 4-8 weeks to produce response and remission from depression. What if a depressed patient needs to recover rapidly for any reason, such as appearing for an examination or interview, attending a family event such as a wedding, performing on stage, or merely continuing to work without taking leave which could result in being terminated from the job? In such situations, ketamine may be useful for procuring and maintaining early improvement. Treatment with ketamine could be repeated, as required, as long as the social need persists.

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