New York. If you are in immediate danger or thinking of harming yourself, stop reading and reach a person now: call or text 988, the Suicide and Crisis Lifeline, which is free, confidential, and available at any hour. Everything that follows is written for the calmer days, when a patient and a family are trying to understand what to do about a depression that has not lifted. But no article is a substitute for a hand on the phone in a crisis.

Depression is one of the most common and most treatable of serious illnesses. For a great many people, the first course of care, talk therapy, a standard antidepressant, or both, brings real relief within a few months. The difficulty is that this first course does not work for everyone, and the people it fails have long had the fewest good answers.

What "treatment-resistant" really means

Clinicians use the phrase treatment-resistant depression for a depression that has not responded adequately to at least two different antidepressants, each taken at a proper dose for a proper length of time. By common estimates, roughly a third of patients do not get sufficient relief from those early attempts. That is not a verdict of hopelessness. It is a signal that the search for the right treatment is not finished, and that it may need to move beyond the first shelf of options.

It helps to name the frustration plainly. Cycling through medication after medication, waiting weeks each time to learn whether it works, is exhausting and demoralizing. Much of the recent progress in this field is aimed squarely at that experience.

The doors that have opened

Several newer or newly refined treatments have widened the range of care for stubborn depression. None is a miracle, and each belongs in the hands of a qualified clinician, but together they have changed what is possible.

One is esketamine, a nasal-spray medicine derived from ketamine that the Food and Drug Administration has approved specifically for treatment-resistant depression. It is given in a certified medical setting under supervision, because patients must be monitored for a period after each dose. Related to it is the use of ketamine itself, delivered by infusion in some specialized clinics, an approach that has drawn attention for acting more quickly than traditional antidepressants in certain patients.

Another is transcranial magnetic stimulation, or TMS, a noninvasive treatment cleared by regulators that uses focused magnetic pulses to stimulate regions of the brain involved in mood. It requires no anesthesia and is typically given in a course of sessions over several weeks. For the most severe and urgent cases, electroconvulsive therapy, one of the oldest treatments in psychiatry and much refined from its grim reputation, remains among the most effective options available.

Where to begin

The first step is almost always a candid conversation with a primary care physician or a psychiatrist, who can confirm the diagnosis, review what has already been tried, and weigh which of these paths fits a particular patient. Some of the newer treatments are offered only through specialized programs, such as clinics offering newer depression care, that are equipped to deliver and supervise them safely. A referral from a trusted doctor is the surest way to find reputable care and to avoid programs that promise more than the evidence supports.

A few cautions are worth carrying into any such conversation. These treatments can carry side effects and are delivered in supervised settings for good reason. The research behind some of them is still maturing, and what helps one patient may do little for another. Coverage and cost vary widely, and are fair questions to raise early. A responsible clinic will welcome those questions, describe the evidence honestly, and never pressure a vulnerable patient toward a quick decision.

Reason for measured hope

The larger story here is a hopeful one, told carefully. A generation ago, a person whose depression resisted the first medicines was often told, in effect, to keep trying the same kind of thing. Today the options are broader, the science is moving, and the stigma that kept many people silent is slowly lifting. Depression that has not yet responded is not depression that cannot respond.

If you take one thing from this page, let it be a telephone number. For a crisis, call or text 988. For a depression that will not lift, make the appointment, ask the hard questions, and keep the door open. Help has grown wider than it used to be, and it is worth walking through.