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What Causes Treatment Resistant Depression

What Is Treatment Resistant Depression

Treatment resistant depression causes & treatment

While there isnt a single, universally agreed-upon definition of treatment resistant depression, a patient is generally thought to have it if they havent responded to at least two different antidepressant medications– assuming that both medications were taken at their respective recommended doses and the patient continued taking each medication for a minimum of six weeks.

The biology of depression itself remains somewhat of a mystery to psychiatric researchers.

Depression May Have Causes We Dont Yet Understandwhich May Be Why Antidepressants Dont Work For Everyone

I saw many patients with treatment-resistant depression who told me that friends and family members believed they preferred being depressed, or werent trying hard enough to improve, because their antidepressants werent working. This isnt about a lack of motivation.

Jaskaran Singh, M.D., Senior Director of Neuroscience, Janssen PharmaceuticalsShare

While the biology of depression is still largely a mystery, the most popular theory is that its caused by low brain levels of such neurotransmitters as serotonin and norepinephrine, which are associated with feelings of happiness and well-being. But recent research suggests that these neurotransmitters may not be the lone culpritso antidepressants, which work to increase serotonin or norepinephrine levels, may not be a one-size-fits-all treatment.

One of the more modern theories is that depression creates inflammation in the brain, or that inflammation in the brain creates depression, Dr. Papp says. Traditional antidepressants only affect neurotransmitters, so this may be why some patients dont respond to them.

Whether or not this turns out to be true, what we do know is there’s still no guaranteed fix for the problemwhich can be frustrating for both patients and their loved ones.

How Lamictal May Treat Anxiety

To determine how lamotrigine may alleviate symptoms of anxiety, its necessary to examine its mechanism of action. Although the mechanism of lamotrigines action isnt fully elucidated, research indicates that it functions predominantly as a presynaptic inhibitor of voltage-gated sodium channels whereby it stabilizes neuronal membranes and inhibits the release of glutamate. Most would speculate that modulation of voltage-gated sodium channel activity and the corresponding downstream effects associated with this modulation generate the majority of its anxiolytic effect.

Additionally, some studies suggest that lamotrigine modulates voltage-gated calcium channels, enhances GABA, and inhibits serotonin reuptake each of which may also contribute to the attenuation of anxiety. That said, it is reasonable to assume that the significance of anxiolytic benefit derived from lamotrigine will be contingent upon the underlying neurochemistry and physiology of the user. Persons with anxiety who exhibit abnormalities in the neurochemical systems targeted by lamotrigine should be expected to derive more substantial anxiolytic benefit than others.

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Does Lamotrigine Interact With Any Medications Or Other Substances

Certain other drugs can affect the way lamotrigine works in your body by decreasing its effectiveness or delaying its excretion from your body. These include hormonal birth control methods, estrogen-containing contraceptives, hormone treatments, the antibiotic rifampin, seizure medications such as phenobarbital, and valproic acid, which is also used to treat bipolar disorder.

Your doctor will carefully prescribe and monitor your dosage when lamotrigine is taken with other treatments. Avoid alcohol, cannabis, and other substances that can increase dizziness or drowsiness while taking lamotrigine. To rule out dangerous side effects, discuss all other medications or mind-altering substances you consume with your doctor before taking lamotrigine.

One recent British study found that folic acid supplements can cancel out lamotrigines benefits . No one expected that result, as folic acid usually helps depression, and other medications, like valproate , says Dr. Aiken. More research is needed before we can fully trust this result, but until then, we recommend taking lamotrigine without any folic acid supplements, including those found in multivitamins. Once youre doing well on lamotrigine, if you decided to add folic acid, watch out for a potential loss of benefits.

The Toll Of An Untreatable Disease

Treatment Resistant Depression (TRD) Survey  Mood ...

Gerard knows the difficulties of this disease better than most. A veteran living with depression and suicidal ideation, he has tried almost every treatment modality available to find relief. Ive taken most categories of antidepressant medication, undergone transcranial magnetic stimulation, attended multiple IOPs , and I go to therapy a couple of times a week, Gerard explains. He said some therapies provided relief for a while and then stopped. Others never really helped, and some even felt actively counterproductive.

For Gerard, his illness meant that work was no longer an option. My depression amplifies exponentially when I try , he explains, which sucks, because Id like toI dont know where I would be if I had to work to keep a roof over my head and food on my plate. Realistically, Id probably be dead already.

For those less financially independent, the chronic stress of balancing full-time work with variable levels of cognitive function makes for a precarious situation. Gerard continues, Part of the problem is that our society isnt structured to accommodate someone working who has good days and bad days. You can either be scheduled or you cant, or youre just flat out expected to show up every day, regardless of illness and symptoms. Even worse, this chronic stress can also cause structural modifications to the brain that often exacerbate depressive symptoms.4

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Additional Forms Of Medication Or Psychotherapy

Finding two medication treatments to be ineffective or too severe does not mean that all psychopharmacological options are inapplicable in your case. That said, it is important to consult with a licensed medical health professional when deciding between different types of medication.

When prescribing a patient their first type of antidepressant, many mental health practitioners prefer to start them on medication belonging to the selective serotonin reuptake inhibitors family. SSRIs appeal lies in their tendency to offer safe and effective results to patients with depression. However, despite their advantages, SSRIs are not for everyone and may either insufficiently alleviate depression symptoms or cause intolerable side effects. Side effects of SSRIs may include nausea, weight gain, or sexual dysfunction. In cases like these,additional types of medications should also be considered.

Serotonin norepinephrine reuptake inhibitors are another type of medication that has been shown to offer similar levels of efficacy to that of SSRIs. SNRIs similarly tend to cause the same side effects of SSRIs, but at lower levels of severity. For this reason, patients who found the side effects of previous antidepressant treatments to be too adverse may be more inclined to consider SNRIs.

Where To From Here

There is thus one fundamental area that contributes greatly to putative TRD: poor diagnosis, which inevitably leads to poor treatment. Within these domains, responsibility falls to both clinicians and researchers to improve patient outcomes.

Research must also continue to test the validity of DSM diagnoses and diagnostic criteria. The fact is that our current diagnostic system is not perfect, and it is imperative that we work to improve it if we want to improve patient outcomes. The advent of modern technologies means that now more than ever we can test the biological validity of diagnoses. As such, research should not only consider studying the effects of medications on homogeneous symptom subgroups, but also examine whether such subgroups differ in neurocircuitry, genetic profiles and biomarkers, with the aim of identifying distinct phenotypes that are likely to respond differentially to treatment.

Fig. 1 An algorithmic approach to the diagnosis and treatment of depression.

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Explore Other Forms Of Therapy

Many people with depression benefit from psychotherapy, or talk therapy.

In fact, research has found that a combination of psychotherapy and antidepressants is more effective at treating the symptoms of depression than medication alone.

Therapy for depression often involves identifying distorted thought processes, changing the way that you think and behave and learning new skills for coping with your symptoms.

If your depression is persistent or simply doesnt improve, your mental health provider may look into different types of psychotherapy. These may include:

Just like with antidepressants, you may need to try several forms of therapy before finding one that works well for you.

Make sure to inform your mental health provider if you feel like a certain form of treatment doesnt feel effective.

What Works What Doesnt

Therapy for treatment-resistant depression

Clinicians must maintain a delicate balance when pursuing treatment options to avoid compounding their patients stress. Although new antidepressant treatments are frequently the focus of news, the onslaught of information can be encouraging but also overwhelming for patients like Gerard. Clinical trials and observational studies are ongoing for a number of new treatments for TRD, including serotonergic psychedelics , atypical antipsychotics, ketamine, deep brain stimulation, and electroconvulsive therapy.5

In LSD trials, researchers suggest that psychedelic-induced 5-HT2AR signaling creates a state of neural plasticity wherein patients can observe the richer context of their world in essence, seeing the forest through the trees and allowing them to revise some of their cognitive biases that lead to depressed thought, rumination, and suicidality. Treatment with psychedelic agents has been shown to be associated with reduced depressive symptoms, lower suicidality, and less psychological distress in patients with recurrent depression or TRD.5

This same logic model supports the effectiveness of cognitive-behavioral therapy, intensive short-term dynamic psychotherapy, and interpersonal therapy, all of which have demonstrated effectiveness at decreasing depression in people with TRD.6

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Stimulants As Treatment Of Treatment

The stimulants most commonly used for treatment-resistant depression include:


Lamotrigine is an anticonvulsant medication used to treat epilepsy. It can also be prescribed as a mood stabilizer in those with bipolar disorder as a replacement for Lithium, which has been relatively under-prescribed in recent years.

Studies have shown that the mood-stabilizing component of Lamotrigine is effective in treating treatment-resistant depression. The drug works by accelerating the onset of antidepressant action.


Ritalin is a trade name for methylphenidate. Some doctors prescribe Ritalin for treatment-resistant depression, but it is typically a stimulant used to treat attention deficit hyperactivity disorder and narcolepsy.

Although the adjunctive use of psychostimulants like Ritalin is still being investigated for the treatment of treatment-resistant depression, there is no clear evidence that methylphenidate is effective at easing the symptoms. Although some promising results were seen in case studies, controlled studies have not demonstrated significant improvement in patient outcomes. As such, most doctors do not recommend Ritalin as a first-line treatment for depression. You should never take methylphenidate medications without guidance from your doctor.


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The Causes Of Treatment

Depression is one of the most prevalent mental illnesses in the United States, with at least 21 million Americans experiencing a major depressive episode each year. Unfortunately, about 30% of those who receive treatment for depression do not see the expected results, leaving them with symptoms that continue on despite their efforts. When this occurs, it is known as treatment-resistant depression or TRD. Many people who experience this condition are left wondering: What are the causes of treatment-resistant depression?

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Trd Is Treatable And Help Is Available

Most people with treatment-resistant depression realize the term living with depression is an oxymoron. Battling with depression, surviving with depression, or existing with depression are more accurate at times.

While there are holistic and mindful practices to handle depression, these often are not enough to cure symptoms completely.

Choosing to find a treatment that can reduce and relieve your treatment-resistant depression symptoms is the first step to living your life again. Understand that your brains treatment resistance is not your fault, and there is nothing you have done wrong.

Fortunately, there are steps you can take to be proactive, and improve your quality of life. Even if youre living with treatment-resistant depression, contact us, to find out how we can help you today!

How Stimulants For Treatment


Stimulants are often used for treatment-resistant depression, usually along with another oral antidepressant, such as an SSRI.

Stimulants and psychostimulants for treatment-resistant depression have been used in addition to conventional antidepressants for decades, and with great success. In a study carried out on those with treatment-resistant depression, 38 out of 65 patients showed significant improvement in response to psychostimulants. Despite concerns in the medical field, none of the subjects in this study showed serious side-effects or developed drug dependency.

This doesnât mean that stimulants are always safe, or that they always work. These kinds of medications can have severe side-effects and dangerous interactions with other drugs, so they must always be taken under guidance from a medical professional.

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Esketamine Decreases Suicidal Thoughts

Conventional antidepressants may actually increase suicidal thoughts at the beginning of treatment, especially in children and young adults. Esketamine is the only drug besides lithium, a drug commonly prescribed for bipolar disorder, thats proven to decrease suicidal thoughts, says Kaplin. Although esketamine isnt currently approved for this purpose, the FDA is considering it.

The Emergence Of Alternative Research Designs

A substantial weakness of the design of current RCT is the insufficient attention to previous treatments aside from response rates, with particular reference to iatrogenic comorbidity . Patients are included in a trial as long as they meet certain inclusion criteria as to their current conditions. The comparison between treatment groups is thus flawed by a randomization process that does not take into account these variables .

An intervention can either be evaluated by a single large trial or by a series of smaller trials . The standard of therapeutic trial in psychiatry is nowadays represented by the large, multicenter RCT with broad inclusion criteria , but little attention is devoted to the clinical history of patients . Not surprisingly, the conclusions that can be drawn by these trials are often very limited. The idea that randomization in trials may eliminate unmeasured confounders clashes against the effects of iatrogenic comorbidity. If we peruse the literature for clinical studies concerned with samples homogeneous for treatment history, we may find out that we do not even have adequate information from observational studies or open therapeutic trials. Small trials on carefully defined populations may actually provide important clinical information that is immediately helpful to the clinician encountering that specific patient. This strategy would constitute a paradigm shift in psychiatry.

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With A Nudge From Ai Ketamine Emerges As A Potential Rare Disease Treatment

The stubbornly high, and steadily increasing, rate of suicides in the U.S. is one factor driving the shift. In April, the National Institute of Mental Health awarded eight grants to test new ways to reduce suicidal thoughts and behaviors in a fast-acting manner, including ketamine and using magnets to activate parts of the brain.

Overall, an unofficial estimate shows the agencys funding for research involving roughly doubled from $34.3 million in the 2007 fiscal year to $68.5 million in FY 2020, based on a search of the National Institutes of Health RePORTER database. A search for transcranial magnetic stimulation for depression reveals an estimated ninefold increase to $21.4 million over the same period.

Nolan Williams, a psychiatrist and neurologist at Stanford University, received one of the new grants as well as another from the NIMH to study magnetic stimulation in treatment-resistant depression. He said there is a push in the field to to think beyond the typical view of depression, and consider new treatments. Were enhancing view to have a multilevel understanding of the problem, he said. Its about incorporating it into a deeper, more dynamic understanding .

The entire thinking of the approach to treating depression is pretty much confined in that little box, said Lisa Harding, a psychiatrist at the Yale School of Medicine.

The Wreck Of Depression Management

Magnetic Seizure Therapy for Treatment Resistant Depression with Jeff Daskalakis

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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Scientists Have Discovered Common Causes For This Failure To Respond To Treatment An Accurate Diagnosis Is Crucial

Underlying causes can create treatment-refractory mood disorders. Our advanced technology and treatment approaches help the toughest cases of long-term depression.

  • Concussion , and other Traumatic Brain Injury, so-called non-traumatic brain injury
  • Autoimmune illness and other abnormalities of inflammation
  • Inadequate plasticity
  • Stress responses and hormonal imbalances
  • Abnormalities of network recruitment and/or perfusion/metabolism

What Are The Causes Of Treatment

No one knows exactly what causes treatment-resistant depression. It may be a mix of different factors, many of which are beyond your control.

The causes of treatment-resistant depression might include:

  • Not taking medicines correctly: For example, skipping doses or not staying on a treatment regimen for a long enough period of time. Alternatively, you may need a higher dose than what was initially prescribed.
  • Drug interactions with other medications: You should talk to your doctor if you think this is the case.
  • Your genetics: You may be genetically predisposed to major depressive disorder, or your DNA could make certain medicines less effective. Researchers have begun to look into the link between treatment-resistant depression and genetics.
  • Other health factors: Depression can be caused or worsened by existing health issues, such as thyroid problems, cancer or heart disease. It’s important to get tested for underlying conditions so that you can seek the appropriate treatment.
  • Misdiagnosis: Some people think they have treatment-resistant depression, but their symptoms are a result of another condition like bipolar disorder, anxiety or a substance-induced mood disorder.

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