Antidepressants For Treatment Resistant Depression

Experts Explain The Reasons Medication Doesn’t Always Work And What You Can Do About It

Article by:

• Farah Fazel, PsyS

As if depression wasnt insidious enough, allow us to introduce you to its fickle, evil twin: treatment-resistant depression . A major depressive disorder, TRD describes depression that has failed to respond to at least two different antidepressant treatments. Anyone who has experienced depression knows how inescapable and hopeless it can feel. TRD compounds that problem, making it difficult for patients to find a treatment that offers lasting relief.

You might imagine thats pretty rare, right? Wrong. Up to one-third of adults with major depression battle symptoms that dont get better with treatment. Many people struggle to find the medication thats right for them, while others never respond to your standard antidepressants. According to Alexander Papp, MD, psychiatrist at UC San Diego Health, only 30-35 percent of patients respond to the first antidepressant theyre prescribed.

Strategies To Prevent Relapse

Treatment to prevent relapse is recommended from the first episode, and a preventive treatment of recurrences is proposed beyond the third episode. The presence of residual symptoms should be carefully considered leading to the prescription of a treatment in order to prevent recurrences from the first depressive episode.

Strategies considered to be effective for preventing recurrences are maintained with electroconvulsive therapy and lithium. In the second-line treatment, the experts proposed lamotrigine or quetiapine.

When full remission is obtained, the experts recommend:

• Regularly assessing treatment adherence

• Regularly assessing insertion and social functioning

• Regularly assessing the quality of life,

• Investigating possible illicit drug use.

The promotion of a regular physical activity and satisfactory food hygiene can be proposed as complementary alternatives for the prevention of recurrences.

Which Augmentation Strategy Is Best For Your Depression

It totally depends on your symptoms and what your psychiatrist thinks. You should first get a proper psychiatric evaluation. If you are severely depressed, you should weigh the pros and cons of each option on this list before choosing a treatment. Some people like myself simply would never allow myself to be on lithium or take an antipsychotic. Others that may be less prone to side effects or that are able to put up with more may want to consider those options.

Although I am not a medical professional, my opinion is that obviously cognitive-behavioral therapy should be considered before everything else. If that doesnt work, I would probably try either psychostimulants or eugeroics. If you are addiction prone, those may not be the best options. Thyroid hormone and lithium are two well researched options if you arent responding well to other options. Due to their extreme side effect profiles, I think that antipsychotics should be used as an absolute last resort if absolutely nothing else helps.

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Definition Of Resistant Depression And At

Based on clinical expert consensus, the definition of treatment-resistant depression adopted is the failure of two ADT of adequate duration and dose. The optimal duration is 4 to 6weeks when the targeted dose is obtained

A history of an unresponsive form of depression is considered the main predictive factor of treatment-resistance and should be meticulously considered. Other potentially predictive indicators are considered, including:

• Comorbid anxiety disorder

• Comorbid personality disorders

• Comorbid non-psychiatric chronic and organic disease

The duration of the untreated episode and early or late age at onset of the first depressive episode as well as the illness severity or onset of depression during the peri-menopausal period are recognised as increasing the risk for treatment resistance. Of note, childhood adversity was not explored in our questionnaire, despite it is a well-established prognostic factor for TRD.

Comorbid neurodegenerative, neurovascular or autoimmune diseases are systematically considered to negatively impact the treatment response. Coronary, endocrine and pulmonary diseases, migraines and cancers could eventually limit clinical alleviation.

A Condition With No Agreed

Beyond the above-mentioned ineffectiveness or adverse reactions to at least two types of antidepressants, there is currently no clearagreed-upon definition for treatment-resistant depression. This means that, for example, cases of increased symptom severity or longer duration would not necessarily be considered treatment-resistant.

The lack of a conventional definition makes it more difficult to address the characteristics of treatment-resistant depression, compared to cases of depression that do respond to initial treatments.

That said, the existing definition of rejection of the first two treatments does manage to distinguish treatment-resistant depression from severe depression . This is also distinguishable from long-term instances of depression or dysthymia, which is another depressive disorder whose definition includes longer bouts of depressive symptoms.

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From Ketamine To Esketamine: Proving And Improving

The history of psychopharmacology is unfortunately full of examples of remarkable findings that turn out to be false leads and are not followed through. Not so with the Krystal and Charney findings. Over the two decades since the initial surprising result, numerous careful NIMH-sponsored studies have consistently demonstrated that ketamine rapidly reduces depressive symptoms when given intravenously. Much of this work has been carried out in the NIMH Intramural Research Program on the NIH campus in Bethesda, Maryland, where we support about 600 scientists conducting research on everything from basic neuroscience to clinical trials. After their initial report was published, Dr. Charney joined NIMH as an investigator and recruited Husseini Manji, M.D. and Carlos Zarate, M.D. to build a mood disorders research program in the IRP.

Meanwhile, NIMH-funded scientists around the country, including Dr. Charney, who left NIMH in 2004 to continue his research at the Icahn School of Medicine at Mt. Sinai in New York, carried out additional studies confirming that ketamine was useful in TRD, where it provides relief from depression in about half of patients. Other studies showed that the effects of ketamine last for several days to a few weeks, and that multiple doses can provide continued relief in those who respond.

What Works Best In Treatment Resistant Depression Part 1

What works best when the first antidepressant fails? And the second? Today, we bring you part one of our special series on treatment resistant depression.

KELLIE NEWSOME: Im going to start with two surprising facts about treatment resistant depression. First, you dont have to be very treatment resistant to have this problem. In depression, treatment resistant means the patient failed to have a meaningful recovery on at least two antidepressants. What is a meaningful recovery? A meaningful recovery does not mean 100% remission 70-80% is often used as the cut off here but its the patients life that we are treating, not the rating scale, so what we really mean by a meaningful recovery is that they are once again functioning in their work and relationships and no longer in significant distress.

How good are antidepressants at bringing about this kind of meaningful recovery? Not as much as wed like. Only 1 in 3 people reach full recovery on their first antidepressant trial, and heres a tip it takes longer than the usual 4-week trial for them to reach full recovery. So, as long they seeing some improvement after 4 weeks on an antidepressant, the best step is to continue it and allow those gains to build. How much longer? Another 1-2 months. If we look at all the remitters in the STAR-D trial, 50% required more 6 weeks to remit, and 40% required more than 8 weeks.

KELLIE NEWSOME: But what about ketamine how does that compare to ECT?

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Complementary And Alternative Medicine

The therapeutic role of ethyl eicosapentaenoic acid, an essential fatty acid, as an augmentation agent for traditional antidepressants in treatment-resistant depression has been reported. Puri et al showed that eicosapentaenoic acid improved some symptoms, including suicidal ideation and social phobia, in a single patient with severe treatment-resistant depression. This compound also induced neurobiological changes, such as a 30% increase in the volumetric niacin response, a 53% increase in the relative concentration of cerebral phosphomonoesters, a 79% increase in the ratio of cerebral phosphomonoesters to phosphodiesters, and a reduction in the lateral ventricular volume of the brain. The therapeutic value of L-methylfolate, a medicinal food, is emphasized in patients of Hispanic origin with treatment-resistant depression. The efficacy of other complementary and alternative medicines in patients with treatment-resistant depression needs to be studied because these therapies have minimal adverse effects and their contribution to the management of various diseases is expanding rapidly. Conversely, in modern medicine, of about 65% of patients who discontinue antidepressants, 45% of them do so because of unpleasant side effects. Regarding lifestyle changes, researchers reported positive effects of moderate physical exercise on quality of life in patients with treatment-resistant depression.

Flawed Designs And Unwarranted Assumptions

In clinical practice, adapting the treatment plan to the changing status of the individual patients is a common strategy. It takes into account both the history of previous treatments and the response to those treatments. When Sir Austin Bradford Hill transferred the methodology that had accumulated with randomized trials in agricultural sciences in the first double-blind placebo-controlled study in medicine , the scenario was dominated by the challenges that acute diseases entailed. Tuberculosis was widespread, there were many reports in the literature claiming effectiveness of drug therapy, and the amount of streptomycin that was available was limited . Randomized controlled trials in medicine thus referred to an average patient who fulfilled the criteria for admission and ignored the patients individual history . There were good reasons for the choices: most clinical encounters were for acute diseases, and patients were unlikely to have experienced many treatments before . Today most of the clinical activities are concentrated on chronic disease or non-disease-specific complaints . Yet, the standard randomized controlled trial design is still based on the acute disease model and ideally evaluates therapeutic effects in untreated patients who have a recent acute onset of their disturbances. This is in sharp contrast with the fact that previous treatments may have actually modified the course and responsiveness of the individual patient .

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Other Deep Cerebral Targets For Psychiatric Illness

Four other potential DBS targets for TRD have recently been described based on anatomic and neuroimaging research: the ventral striatum/nucleus accumbens , the inferior thalamic peduncle , rostral cingulate cortex , and the lateral habenula . Treatment at three of these four targets has been tested clinically and has proven safe and effective, albeit in small numbers of patients .

Finally, multiple avenues of research implicate the nucleus accumbens and the frontal dopaminergic projections in the biology of addiction. Consequently, the NAc has been proposed as a potential neuromodulatory target for the treatment of various forms of addiction. One case has been reported that highlights the possibilities. The patient underwent ventral capsule/NAc DBS for the treatment of TRD. One year later, his depression remained severe, but he had spontaneously abstained from drinking after many years of alcoholism .

Rebecca Strawbridge, … Anthony J. Cleare, in, 2018

The Wreck Of Depression Management

The conceptual flaws and the spurious results of the literature have yielded two detrimental clinical consequences. One is the development of drugs geared to treatment resistance, such as ketamine/esketamine , which would not survive the test of a classic RCT in depression. The second consequence has been the assumption that treatment with whatever antidepressant is right in the first place, and failure to respond is entirely shifted upon patients characteristics. Treatment resistance thus calls for switching and augmentation, instead of reconsideration of the process in treatment selection. Fava and Rafanelli have applied the concept of cascade iatrogenesis, that originated in geriatrics , to psychiatric settings. The patient is prescribed an increasing number of medications that, as in the STAR*D trial, in the long run cause other problems and may make the illness refractory. When symptoms of behavioral toxicity are misinterpreted or simply ignored, a cascade of events leading to illness deterioration or its chronic course may result from the choices of the clinician .

An initial cross-sectional examination with a very narrow focus seems to generate a number of decisions that are performed in automatic, as a result of algorithms or guidelines, with few opportunities for modifying the initial judgment.

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Who Is A Good Candidate For Esketamine Therapy

Currently, esketamine is approved for people with treatment-resistant depression. That means youve tried at least two other antidepressants and havent experienced remission or at least a 50% improvement in mood.

For people who havent had success with other antidepressants, esketamine gives them the chance to see what its like to not have depression, says Kaplin. It gives them hope that they can feel better with the right treatment.

Building On Success: Whats Next In Ketamine Research

The job is not done for TRD. Ketamine and esketamine work, but both have significant drawbacks. Many patients experience uncomfortable dissociative symptoms, hypertension, or other side effects for a few hours after administration. Because of these symptoms, as well as the potential for abuse, both need to be administered in a doctors office. These arent medications you can pick up at the pharmacy and take on your own. Dr. Zarate and others are hard at work at finding safer alternatives to ketamine by examining the mechanisms by which it works. One such promising compound, a metabolic product of ketamine, was identified through a collaboration between Dr. Zarate and Todd Gould, Ph.D., of the University of Maryland School of Medicine. A cross-institute collaboration between NIMH, National Institute on Aging, and the National Center for Advancing Translational Science is developing this agent in order to test its efficacy in patients with TRD.

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Principles Of Clinical And Pharmacological Management

Indications for hospitalisation

Hospitalisation is systematically recommended in cases of:

• High suicidal risk

• Failure of three unsuccessful attempts of ADT

• Need for electroconvulsive therapy

Hospitalisation can be considered in cases of:

• Risk of poor adherence to treatment

• Failure of two previous ADT

• Comorbidity with a severe medical condition

• Co-occurrence with other psychiatric disorders

• Lack of adequate familial support

• Intolerance to current medication

• Need for benzodiazepines withdrawal

• Need for monoamine oxidase inhibitors, transcranial magnetic stimulation or transcranial direct current stimulation

The need to introduce a tricyclic ADT, lithium, pramipexole or second-generation antipsychotic is not considered as an indication for hospitalisation.

Adjuvant treatments

For patients with anxious features, the adjunctive use of benzodiazepines or hydroxyzine is systematically recommended. The use of buspirone, pregabalin or an ADT belonging to a different pharmacological class is possible in this indication.

The use of an ADT from the same pharmacological class is not recommended.

For patients with sleep disorders, the adjunctive use of hypnotic is systematically recommended. The use of hydroxyzine, benzodiazepines or an ADT with a different pharmacological profile is possible as an alternative therapeutic option.

Treatments with an ADT action

The following classes or medications are recognised as having antidepressant properties:

Minimal duration of ADT

What Is The Best Treatment For Treatment

If you have tried traditional treatments for major depressive disorder and your symptoms are not abating, then you need to know the best treatment for treatment-resistant depression. Treatment-resistant depression is complex. There is no one, foolproof way to treat this condition. It takes patience, grace, and a lot of support from professionals who are experienced in managing this type of mental health disorder. The first three areas where the work will start are generally medication adjustment, talk therapy, and coping mechanisms.

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When Antidepressants Dont Work: Living With Incurable Depression

For the majority of people, a combination of medication, counseling and neuro therapy effectively treats their depression. Other people may experience depression as a cloud that always hovers, no matter what treatments they try.

For the handful of people who truly have treatment-resistant depression, looking for a cure may be the wrong approach. Rather than seeking to totally eliminate every symptom of depression, a more realistic and productive goal may be to learn how to manage the symptoms of depression and achieve the best outcome possible.

Those who havent had success in treating depression may benefit from seeking help from an experienced mental healthcare professional. While primary care doctors can prescribe antidepressants, for many people, this is just one aspect of effective treatment. A mental healthcare professional that utilizes more comprehensive treatment plans and has up-to-date knowledge on state-of-the-art therapies may be able to better help individuals achieve their desired outcomes.

How Do You Treat Treatment

So how do you treat depression that is, by definition, treatment-resistant? While TRD often predicts poor response to standard antidepressant medications, a history of TRD isnt necessarily a predictor of poor response to electroconvulsive therapy or rapid-acting medications like ketamine or esketamine , says Krystal. To fight TRD, the medical community is embracing an array of methodssome familiar, some totally unexpected:

• Ketamine and esketamine. Originally developed as an anesthetic ketamine quickly produces an antidepressant effect by increasing the amount of neurotransmitters in the brain. Its still used off-label as an antidepressant, but its cousin, esketamine, was approved by the FDA in 2019.

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Ketaminefrom Anesthetic To Depression Miracle Drug

Interestingly, studies from Yale research labs showed that the drug ketamine, which was widely used as anesthesia during surgeries, triggers glutamate production, which, in a complex, cascading series of events, prompts the brain to form new neural connections. This makes the brain more adaptable and able to create new pathways, and gives patients the opportunity to develop more positive thoughts and behaviors. This was an effect that had not been seen before, even with traditional antidepressants.

I think the interesting and exciting part of this discovery is that it came largely out of basic neuroscience research, instead of by chance, says Gerard Sanacora, MD, PhD, a psychiatrist at Yale Medicine who was also involved in many of the ketamine studies. It wasnt just, lets try this drug and see what happens. There was increasing evidence suggesting that there was some abnormality within the glutamatergic system in the brains of people suffering from depression, and this prompted the idea of using a drug that targets this system.

This is why Dr. Sanacora believes that ketamine may be most effective when combined with cognitive behavioral therapy . CBT is a type of psychotherapy that helps patients learn more productive attitudes and behaviors. Ongoing research, including clinical trials, addressing this idea are currently underway here at Yale.