Tag: treatment resistant depression

How to Approach Poor Response to Antidepressants  

What defines Treatment Resistant Depression (TRD)

Stage 1: more than one adequate trial of 1 major class of antidepressants 

Stage 2: Failure of more than 2 adequate trials of two different classes of antidepressants 

Stage 3: stage 2 + TCA 

Stage 4: Stage 3 + MAOI 

Stage 5: Stage 4 + bilateral ECT 

With every medication or neuromodulation procedure used that doesn’t work, the more treatment resistant the depression becomes. 

Antidepressant Response Rates 

Frist Medication Trial: 50% respond and 37% have remission 

Second Medication Trial: Another 29% respond and 31% have remission 

Third Medication Trial: 17% respond and 14% have remission

Fourth Medication Trial: 16% respond and 13% have remission 

The overall cumulative remission rates are 67%, keeping in mind that people who progressed through more treatment stages had higher relapse rates and more residual symptoms including anhedonia, emotional blunting, and lack of motivation.

If someone is having a poor response to medication, what do you do?

We know that bipolar disorder is missed in a significant number of patients who present with depression about one in five will be misdiagnosed. We also know that antidepressants can be mood destabilizing in bipolar illness resulting in mixed features and rapid cycling. Other things that can interfere with response include substance use disorder, personality traits, and PTSD. 

Medical Comorbidities that can interfere with antidepressant response include hypothyroidism, Cushing disease, Parkinson’s disease, cancer, vitamin/nutritional deficiencies, and viral infections 

Psychosocial factors that contribute to treatment resistance 

-Female sex 

-Older Age 

-Single Unmarried (happiness studies indicate that good relationships are very important) 

-Unemployment 

Symptoms that make TRD more Likely 

-Recurrent episodes usually 3 or more 

-Severe depression and inpatient admission 

-Anxiety, Insomnia, or Migraine 

When Your First Choice Fails

There are several approaches

-Switch antidepressant classes 

-Combine antidepressants 

-Add a dopamine blocking medication

-Add L-methylfolate 

-Add Psychotherapy 

-Start Neuromodulation 

What’s the most effective strategy

Hands down the most effective thing to do if a patient has a poor response to the initial antidepressant treatment is to add a dopamine blocking medication. Response and remission rates are much higher, but it comes at the price of increased side effect potential. 

What are the most used Dopamine Blockers in Antidepressant Augmentation

-Quetiapine 

-Olanzapine

-Risperidone 

-Aripiprazole 

-Ziprasidone 

Older patients 65 years and older respond better to aripiprazole augmentation than switch to bupropion, or combination with bupropion. 

Brexpiprazole: 1-3 mg/day Adjunctive for Depression 

Most Common Concerns patients have about being on dopamine Blocking Medication 

-Weight gain 60% of people report this concern 

-Metabolic side effects 

-EPS

-Sedation 

-Akathisia 

-Prolactin-related Effects 

Anti-Inflammatory Medications 

For those with elevated inflammatory biomarkers specifically c-reactive protein there is some emerging evidence that these treatments work. 

-Medications like Celecoxib, Omega-3 fatty acids, statin drugs and minocycline 

-Weight loss 

-Effect Size: 0.55 

-Higher response and remission rates 

-May only work in those with high inflammatory biomarkers 

Glutamate Modulators 

-Ketamine Infusions and Esketamine: both work and a reasonable option if TRD 

-There are several medications in development 

Psychotherapy in TRD

Unfortunately, what we find with TRD is psychotherapy does not prevent TRD, it doesn’t mean there is no benefit it just means future episodes will not be prevented by psychotherapy. On its own, psychotherapy may not be as helpful as we would like in TRD but when combined with medication it does help. That tells us about the importance of evaluating severity of depressive episode.

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Why People with Major Depression Don’t Get Better 

When Someone does not experience remission from major depression, we need to ask ourselves why, and come up with new solutions. This discussion will focus on the treatment of these individuals by first explaining what symptoms predict poor response to treatment and what symptoms of major depression result in the most psychosocial dysfunction. 

What Causes Functional Impairment in Major Depression 

From the STAR*D study we know that only 50% of patients respond to the first antidepressant treatment and only 33% achieve remission. An important question is why, or more specifically what factors result in poor outcomes. 

Contrary to popular belief the medications we use to treat depression work well for some neurovegetative symptoms. Symptoms such as sleep, and appetite improve but the most debilitating symptoms often remain. Consistently Anhedonia and concentration are rated by patients with depression as the most debilitating. These cognitive symptoms such as trouble concentrating, difficulty planning, and poor attention lead to dysfunction at home and work. 

Cognitive Symptoms Impair Work Performance 

We all need to work to live, and depression is a leading cause of disability and poor work performance worldwide. What we know is that subjective measures of cognitive dysfunction are a better predictor of workplace performance than total depression severity. Someone with more severe overall depression scores may perform better at work than someone with perceived cognitive dysfunction from depression. This is one possible reason for a lack of improvement as many treatments do not address cognitive symptoms. 

Anhedonia makes everything Worse 

Possibly the most debilitating symptom of depression is anhedonia. Anhedonia is defined as loss of interest in previously pleasurable activities. A strong predictor of poor antidepressant outcome is the loss of interest. Making anhedonia a primary target of treatment would be wise if we want to improve outcomes in depression. 

We have additional evidence that indicates how important anhedonia is for psychosocial function. Functional improvement is strongly associated with improvement in anhedonia. The improvement in anhedonia had a larger effect on psychosocial function than overall symptomatic response. 

Emotional Blunting Effects on Treatment Outcomes 

While people do not want to be depressed, they also do not want to be emotionally dull. Unfortunately, we know that emotional blunting is reported in nearly half of all depressed patients on antidepressants. This appears to be common to all monoamine antidepressants with bupropion having the lowest reported risk. Emotional blunting cannot be totally accounted for as just a side effect of treatment, it’s also a symptom of depression. However, the point remains the same emotional blunting results in poorer quality of remission. 

Doctors Are Too Medically Oriented

The world of psychiatry is very different from other medical specialties. Psychiatry is really art based in science and if you try to approach mental health treatment from a strictly scientific basis you will never help anyone. When patients and physicians are asked to rank the symptoms of depression, they believe are most important, the lists do not match up. 

Patients focus on restoration of positive affect by ranking things such as meaning and purpose in life, enjoyment in life, satisfaction with oneself as the top three most important things to address in depression. Clearly what should stand out to you here is that medication is unlikely to improve any of these factors. 

Doctors rank depressed mood, hopelessness, and anhedonia as their top three symptoms to address. These symptoms are far better addressed by medication than the ones listed by patients although you could argue that hopelessness and anhedonia are difficult to treat with medication. 

The effect of Loneliness on Health Outcomes

I’ve talked about this before and it continues to be a major concern in our modern world. We are the most connected we have ever been as a society with the advent of social media and the internet, yet no one feels connected. This is an existential crisis for all of us and I haven’t heard many good solutions. Time and time again we go back to the same things such as the internet and social media to feel connected and they continue to let us down. Not only is this emotionally taxing, but it’s also effecting our physical health as well. Here is yet another example of something that is very important for depression treatment outcomes that medication cannot fix. 

Conclusion

What does this all mean? Should we stop attempting to use medication for the symptoms of depression? For me these findings indicate we need to screen more carefully for these specific symptoms that result in poor outcomes. We need to improve our psychosocial treatments to help people address ways to enhancing meaning and purpose in their lives. We need to recognize the limitations of medications. Medications have a place and do address some of the symptoms associated with depression, they just aren’t the ones patients believe are most important in their lives. 

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SAINT The Best Transcranial Magnetic Stimulation (TMS) Therapy Protocol Ever  

We all know how difficult treatment resistant depression (TRD) is for both the patient and the clinician. Wouldn’t it be great if we had a noninvasive method to treat these cases with better efficacy than ECT? What if I told you there is a new type of TMS that leads to remission in 80% of the most difficult to treat cases of depression? Would you be interested? Let’s Find out. 

Introduction:

SAINT stands for Stanford Accelerated Intelligent Neuromodulation Therapy, try saying that one three times fast. 

This is not a new concept as SAINT uses a noninvasive neuromodulation therapy (TMS) in patients with treatment resistant depression and it has shown some real promise in that area.

Treatment resistant depression (TRD) can affect up to 30% of patients with major depressive disorder and as you might expect it’s hard to treat these cases. When a patient reaches this point, things like off-label medication prescribing, ECT and Ketamine are used. However, the FDA just approved a new version of TMS that is reported to have an 80% remission rate in these patients. 

The approval came quick as this device has received breakthrough status by the FDA based on the impressive results from study that included 22 participants with TRD. 19 of the 22 participants achieved remission which in terms of percentage was 86.4% of participants. This is substantially better than other treatments for TRD including ECT which come in around 50%-70% depending on the study you read. 

What Is SAINT?

SAINT was first developed at Stanford University. What sets this TMS procedure apart from other methods of TMS is the intensity of treatment (10 sessions per day) carried out over the course of 5 days. Each session is 10 minutes in length. The intelligent portion of the name has to do with the use of MRI/fMRI-guided theta burst stimulation ensure proper placement of the coil on the dorsal lateral prefrontal cortex. 

This device made it out of the academic arena and is now being distributed by a private start up company called Magnus Medical. You can get on the waiting list now to purchase one of these machines if you feel compelled to do so after this talk. To be clear I have no affiliations with the company.

What Research Lead to FDA Breakthrough Status Approval?

In general devices are not held to the same standard as medications when we are talking about FDA approval. It’s much easier to get a device approved. 

The initial work was carried out with an open label format which is usually considered a lower form of evidence when compared to randomized controlled trials. The research group eventually published a randomized controlled trial in the American Journal of Psychiatry which is largely what allowed SAINT to gain FDA approval. In this study 32 participants with TRD were randomized to active treatment or sham. In this study they used percent reduction from baseline MADRS score 4 weeks after treatment which was found to be 52.5% in the SAINT group and 11.1% in the sham group. The remission rates in this study were 79% for the treatment group compared to 13.3% in the sham group. 

These are significant results in the most difficult patient population to treat. It’s important to point out that these participants had 10 hours of contact with the treatment team per day and the number of participants in the study was small. Both are confounding factors, but using sham treatment helps because most participants were not able to tell if they received the treatment or sham. The one thing that was more common in the treatment group was headaches which may have altered them to which groups they were randomized into.

The authors justified the low number of participants because they achieved a very large effect size with statistical significance without additional participants. What is currently missing from the research is a large randomized controlled trial conducted independently of the research group who designed the protocol (something to look out for in the future). 

Mechanism of Action (MOA)

One question you may have been thinking about is how does TMS work and what is the proposed mechanism of action for SAINT? 

TMS is a noninvasive method of modulating specific areas of the brain by generating a magnetic field which induces neural cell membrane potentials to depolarize in the brain under the coil. Placing the coil in the correct location is critical and there is a 30% chance of missing that location when MRI is not used to map the exact location of the dorsal lateral prefrontal cortex. 

SAINT is thought to alter brain connectivity and increase neuroplasticity in ways that traditional forms of TMS do not. The preliminary evidence suggests connectivity between the amygdala, insula, and medial frontal gyrus is altered in a meaningful way resulting in the improvement in depressive symptoms. Studies are underway to assess the MOA further. 

How Does SAINT Differ From Other Forms of TMS? 

First it differs in the time frame, it takes place only 5 days while most other forms of TMS take a full 6 weeks to complete. The treatments during those 5 days are intense, it requires 10 treatments per day while standard TMS is usually once per day. 

The time for each treatment in the SAINT protocol is much shorter lasting approximately 10 minutes compared to the 20 to 45 minutes usually required. 

There are three established types of TMS that differ in the time it takes to complete the treatment session. 

-The first one on the market was the figure 8 coil which took 45 minutes to complete each session 

-The H coils were invented by Brainsway and these sessions take 20 minutes 

-Theta-burst stimulation: only take 3 minutes, and this is the one that the SAINT protocol uses 

The next question is where to place the coil and how to place it. Traditionally the coil is moved around until the thumb twitches, this is the so-called thumb center, and we can look at the homunculus drawing and see how large the thumb center is. Traditionally we would measure 7 centimeters away from the thumb center and that should be the left dorsolateral prefrontal cortex. This method is not very accurate missing the mark approximately 30% of the time. To fix this problem the SAINT protocol uses MRI guided imaging to be sure the coil placement is accurate. You can also use EEG or PET scans to guide placement. 

Conclusion

-While I’m glad there is innovation in TMS treatment, and the results thus far have been impressive we have to keep in mind this machine is now being marketed by a startup company and has left the world of academia. 

-It’s unclear if you need their machine to produce similar results as theta burst TMS already exists and MRI guided placement of the coil on the dorsal lateral prefrontal cortex exists as well. The company claims they have developed an algorithm for placing the coil that is unique and this claim will need to be investigated further once the machines are available. 

-Another concern is most of the research has been published by the same group that designed the protocol and has not been reproduced in large RCTs independently. 

-My final concern is regarding the application of this treatment for the average patient. It requires a full 5 days and 10 hours of treatment over the course of the 5 days. This may or may not be feasible for the average patient with treatment resistant depression. We haven’t even talked about what this intensive treatment will cost and if insurers will pay for it, another potential barrier. 

-I would also like to see this go head-to-head in a study with Ketamine infusions and ECT. 

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Pramipexole for Treatment Resistant Depression

How to use Pramipexole

  • Selective D3 agonist thought to be related to hedonic drive. 
  • FDA approved for Parkinson’s disease and restless leg syndrome 
  • 5 randomized controlled trials indicating effectiveness in depression as monotherapy or adjunctive therapy and in bipolar disorder as adjunctive therapy with a mood stabilizer 
  • Side effects; nausea, hypotension, and fatigue, titrate slowly and give the dose at night 
  • Start with 0.125-0.25 mg QHS and rise by 0.25 mg every 5-7 days towards a target dose of 0.75-2 mg QHS 
  • Watch for hedonistic homeostatic dysregulation (HDD) including pathological gambling and shopping

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5 Stage Method for Treatment Resistant Depression (TRD)

I get a lot of questions that go something like this, I’ve been on X, Y, Z medications and nothing seems to help. It seems that what most are asking about is what is the algorithm for treating depression and when does it become treatment resistant. This video will provide a look at what treatment resistant depression is and provides a 5-stage strategy to medication selection.  

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