Treatment-Resistant Depression

Treatment-resistant depression is surprisingly common. By understanding the reasons for treatment resistance and ways to overcome it, effective therapies can be explored.

Depression is a commonmental health disorderthat has a serious impact on people’s lives, making it difficult for them to carry out even basic functions at work and at home. In fact, theWorld Health Organization(WHO) has identified depression as the leading cause of disability worldwide.

Statisticsshow that treatment-resistance is a serious problem. About one-third of depressed people turn out to havetreatment-resistant depression. That’s a lot, considering that16.9%of people in the U.S. developdepressionat some point in their lives.

People who are treatment-resistant must not give up hope. There are manytreatment-resistant depression optionsfor achieving remission and returning to healthy and happy function. Unfortunately, many people with depression do not seekhelp, and some people with treatment-resistant depression give up seeking help.

What Is Treatment-Resistant Depression?

There is no agreed upon definition of treatment-resistant depression. This is because every person affected by depression can have a different set of symptoms. The Standard Diagnostic Manual (DSM-5) showsthere are more than 1,500 different possible combinations of symptoms that qualify for amajor depressive disorderdiagnosis.

People who are treatment-resistant are usually not resistant to treatment altogether. Rather, they are not yet matched to the correct treatment that suits their particular biological makeup, the rootcauseof their depression and their symptoms. As such, thecause of treatment-resistant depressionusually comes from the inability to find the right treatment.

Treatment-resistant depression statisticshave been described bya large studyas seriously damaged by the lack of universal diagnostic criteria. However, data from aU.S. STAR*D studyshows that more than half of all patients do not attain remission from their depression after the first line of therapy, and one-third did not achieve remission after four courses of therapy.

Diagnosing Treatment-Resistant Depression

There is no objective diagnostic test for depression, such as a blood test, that can diagnose and measure depression and response to treatment. Traditionally,treatment-resistant depression criteriainvolve failing to achieve at least a 50% decrease on adepression rating scale. However, this definition is lacking because many people who achieve an adequate score reduction still have bothersome residual symptoms.

Amore general definitionstates that depressed people who have not had an adequate response to two antidepressant medication treatmentsare considered to have treatment-resistant depression.

Prior to diagnosing their patients with treatment-resistant depression, prescribers should first:

• Reassess the diagnosis:Make sure it is really depression and not a medical condition that has symptoms similar to depression (such as anemia, hypothyroidism or vitamin B12 deficiency)
• Assess for substance use:Use ofalcohol or drugs of addictioncan negate the effects of antidepressant treatments
• Assess for other mental health disorders:Mental disorders may co-occur with depression and impact treatment effectiveness (such aspost-traumatic stress disorder)
• Assess for other medications:Certain drugs, including over-the-counter or herbal medications, may be interfering with antidepressant medications
• Check for adherence:Many people do not take their medications as prescribed due to forgetfulness, cost or side effects

Getting Help for Treatment-Resistant Depression

There are many differenttypes and subtypes of depression. One characteristic that is common to all types is the loss of motivation to do anything, including self-care. As such, people with depression are very likely to not bother seeking treatment.

Many people with depression may not recognize that there is something wrong, and they may just think that they are “sad” or “down.” However,depression is much more than just having the blues. It is a physical illness with biochemical, physiological and hormonal changes in the brain and body that make the individual very ill.

Even family members may discourage seeking help by telling a depressed loved one to just “get over it.” Depression is not something that people can “just get over” or think their way out of. People need to seek and accepthelp for depression. The illness can persist for months and years if left untreated, and it can result in suicidality or other physical and mental illnesses. As well, it is a common pathway to substance addiction.

People need to continue seeking help if their depression is resistant to initial attempts at treatment.Help for treatment-resistant depressionis available, but it may require specialized care and some trial-and-error.

Feelings of depression or anxiety can lead to suicidal thinking.If you or a loved one is experiencing suicidal thoughts or tendencies, call theNational Suicide Prevention Hotlineat1-800-273-8255.

Medication Options

When consideringmedication optionsfor depression, the usual starting point isselective serotonin reuptake inhibitor(SSRI) medications. If success is not achieved after trying one of these, changes will be made to see what does work. Finding the righttreatment-resistant depression medicationis a matter of time and patience. There are several ways to explore medication options:

• Give current medications more time.Antidepressant medications take different amounts of time for their therapeutic effects to begin. Typically they taketwo to three weeksbefore they work.Studieshave shown it takes an average time of 13 days for therapeutic effects to begin and 20 days for the full effects. Waiting six to 12 weeks before making any changes to medications is a common practice among prescribers. However, some researchers find that if no effect is observed at two weeks, then response at six to 12 weeks is unlikely.
• Increase dosage.Prescribers usually begin patients on the lowest effective dose. An inadequate response usually results in a dosage increase before making other changes. Eachdose increaserequires waiting weeks to see the response. Knowingwhen to increase the antidepressant dosageis a matter of close communication between the individual and the prescriber.
• Switch medications.After an adequate trial at the maximum effective dose of the first antidepressant medication, the usual practice isswitching antidepressants. This may be a different medication from the same drug class or a medication from a different drug class.
• Add another medication.Adding a second medication to the failed medication is one option after a trial of switching medications. These may be other medications with antidepressant effects (such as a mood stabilizer, antipsychotic) or a non-antidepressant that enhances the action of the antidepressant (such as thyroid hormone).

The use ofstimulants for treatment-resistant depressionis a controversial topic. Alarge review of research evidenceshows its effects on depression appear to be limited, and tolerance and addiction issues are a significant risk. There is little research data to guide prescribers on when to usestimulants for depression.

It has been suggested that it may be effective to use the opioid antagonistbuprenorphine for treatment-resistant depression. A recentreview of the research evidencehas shown that buprenorphine may have some merits as an antidepressant, but much more research is needed before any recommendations for regular use can be made. However, for people who are recovering from opioid addiction and wish to useopioid replacement therapy, buprenorphine may be an appropriate choice if they have depression.

Psychotherapy Approaches

Psychotherapyis an effective treatment option for depression, especially if used along with medications. Of the various methods of psychotherapy,cognitive behavioral therapy(CBT) is by far the best-studied andmost used.

There are other types of psychotherapy that have been used in treating depression, such as cognitive therapy, behavioral therapy and interpersonal therapy. CBT incorporates elements from all of these. CBT is also useful because it is effective for a number of other mental health disorders that commonly co-occur with depression, such assubstance use disorders.

Data from a systematic reviewof clinical trials shows that CBT reduces depression symptoms by around 45% to 50%.

Neurostimulation Procedures

Neurostimulation procedures involve applying some form of energy directly to the brain to create an antidepressant effect.

Many kinds of neurostimulation therapy are currently in use or on the horizon for treatment-resistant or severe depression. Electroconvulsive therapy and transcranial magnetic stimulation are the current gold-standard neurostimulation therapies, while vagus nerve stimulation is also widely used. Several other neurostimulation techniques have not yet been well studied and are not commonly used. These include magnetic seizure therapy (MST), transcranial direct current stimulation (tDCS) anddeep brain stimulation (DBS) for treatment-resistant depression.

• Electroconvulsive therapy (ECT).ECT has been used in thetreatment of major depressionfor more than 75 years.ECTis themost effective neurostimulation procedureand the most commonly used therapy for treatment-resistant depression when medications and psychotherapy have failed. The individual is given a general anesthetic and a muscle relaxant, and then an electric current is applied to the scalp to induce a seizure. Treatments are given three times a week until effective and then tapered off over several weeks. Follow-up maintenance treatments are done once every three to six weeks. Unfortunately, even with maintenance treatments and medications, the relapse rate is about 37% followingECT for depression.
• Transcranial magnetic stimulation (TMS). Transcranial magnetic stimulation (TMS) therapy for depression and for treatment-resistant depression has been in use since the 1980s. It has about a 60% response rate in people with treatment-resistant depression and has very few side effects. Unfortunately, its antidepressant effects often do not persist. TMS is used in along with medications, psychotherapy and sometimes other neurostimulation procedures.
• Vagus nerve stimulation (VNS).The FDA approvedvagus nerve stimulation(VNS) as atreatment for depressionin 2005. From the brain, the vagus nerve goes down both sides of the neck to the chest, where it connects with the heart and many other internal organs. At its origin, the vagus nerve projects to many areas of the brain, making it a perfect target for therapies involving brain stimulation. While the patient is under anesthesia, theVNS stimulatoris implanted on the vagus nerve by a neurosurgeon. A wire is wrapped around the nerve and a pulse generator is implanted in the chest. Treatments are then done (usually about five times per week) by passing a wand over the stimulator.Data on response ratesare varied, butVNS for depressionappears to have a response rate of up to 30% to 40% after 10 weeks of treatments and 4% to 44% after 12 months.

Experimental Therapies

The genetics of depression are currentlybeing researched, with a large focus on treatment-resistant depression.As of 2019, more than 80 genes that are related to depression have been identified, including a gene that seems to cause severe and recurrent treatment-resistant depression (the 3p25-26 gene).

As research into the genetics of depression progresses, new therapies will follow. By identifying depression genes, prescribers will be able to tailor therapy to each patient’s specific depression. This will likely make therapy much more effective and timely. It is almost certain that thenewest treatments for drug-resistant depressionwill be based on genetics.

Gene therapy – where clinicians replace defective genes with healthy ones – is already being used for certain diseases. In fact, the technique isalready being usedin studies on mice with depression. It is likely that gene therapy will becomeused to prevent and treat depressionas the technology for gene therapy and knowledge about depression genetics progress.

Esketamine for Depression

In early 2019, theFDA approvedthe use ofesketamine nasal spray(Spravato) for use in adults with treatment-resistant depression.It is only used in conjunction with a standard antidepressant medication. Esketamine is related to the drugketamine,which is an addictive controlled substance.

Ketamine has received a lot of attention for its effectiveness against depression, leading to much research onketamine and depression. The nasal spray version of ketamine offers a safer and easier way to administer ketamine, which must otherwise be injected intravenously.

Like ketamine, esketamine causes serious side effects:

• Impaired judgment, attention and thinking
• Slowed reaction times
• Sedation, lethargy
• Feeling high
• Vertigo (extreme dizziness)
• Vomiting
• High blood pressure
• Anxiety
• Fetal defects

As such, esketamine must be used with great care, and it is not a medication that is taken home. It is administered by a physician in the clinic, and the patient cannot leave the clinic without obtaining medical clearance. There must be someone there to drive the patient home because it is not safe to drive a vehicle until the next day.

Lifestyle Modifications

The prevalence of depression has been increasing since the 1980s. While this may be related to improved public awareness and diagnosis, it almost certainly has much to do with the increasingly fast-paced and stressful lifestyle found in modern society.

On top of work and lengthy commutes, people are becoming increasingly disconnected from interpersonal relationships due to distractions such as social media, streaming entertainment and other online activities. In addition to the rise in obesity, increased sleep deficiency, poor diet, lack of physical activity and increased stress have raised the likelihood of depression. The steadyincrease in alcohol and substanceuse has also been a major factor in the rise of depression rates.

Significant evidencehas shown that self-care, healthy lifestyle choices and improvements in work-life balance can have significant positive effects on mental health and mood. In fact, The Recovery Village takes advantage of this well-established fact by usingrecreational therapyas part of a comprehensive treatment program for depression and other mental health and substance use disorders.

Finding better physical and mental health through a healthy diet, adequate exercise and proper sleeping habits improves people’s health and happiness in a measurable way. Finding a better work-life balance to improve leisure, foster social engagement and reduce stress can also have noticeable effects. Finding time for healthy practices like mindfulness and relaxation techniques can also improve a person’s ability to cope with stress and reduce the chances of depression and substance use.

Prognosis and Outlook

Most people with depression are easily treated with simple medications and psychotherapy. However, it can be hard tolive withtreatment-resistant depression, which can lead to suicidal thoughts or behaviors. Fortunately, there is a way to recover.For those who are treatment-resistant, it’s a matter of working with their care provider to find a treatment that works, even if it takes some time. It is very important that all underlying factors be identified, especially other mental health disorders and substance use. A thorough initial assessment is key.

The Recovery Village offers professional assessment andtreatment programsfor depression and co-occurring substance use disorders. Our trained professional staff members have the expertise and experience needed for treating even complex cases.Contact usfor a confidential discussion with one of our counselors if you have concerns about yourself or a loved one.