How Can We Better Understand and Treat Resistance to Psychiatric Medications?

What you need to know

• Treatment resistance affects 20-60% of patients with psychiatric disorders and is associated with significant disability and healthcare costs.
• There is a lack of consistent definitions and criteria for treatment resistance across psychiatric disorders.
• New treatments targeting different brain mechanisms are being developed for treatment-resistant psychiatric disorders.
• More research is needed to understand the biological basis of treatment resistance and develop personalized approaches.

What is treatment resistance in psychiatry?

Treatment resistance in psychiatry refers to when a person’s mental health condition does not improve adequately despite receiving standard treatments. This is unfortunately common, affecting about 20-60% of patients with conditions like schizophrenia, depression, bipolar disorder, and obsessive-compulsive disorder (OCD).

When someone has treatment-resistant illness, it often means their symptoms remain severe and disabling even after trying multiple medications or therapies. This can be extremely frustrating and discouraging for patients and their families. It also leads to higher healthcare costs and use of resources.

The concept of treatment resistance in psychiatry has been around for many decades. However, research in this area has increased significantly in recent years as we’ve recognized how common and impactful it is. Still, studies on treatment resistance make up less than 1% of psychiatric research overall. Given how prevalent and burdensome it is, more work is clearly needed in this area.

How is treatment resistance defined?

One of the challenges in addressing treatment resistance is that there is no single agreed-upon definition that applies across all psychiatric disorders. The authors of this paper reviewed 23 different guidelines and consensus statements on how treatment resistance is defined for various conditions. They found three key components that are generally included:

1. Confirming the correct psychiatric diagnosis has been made
2. Ensuring the patient has received adequate treatment (proper medication doses for long enough)
3. Determining there has been inadequate improvement in symptoms despite treatment

However, the specific criteria used can vary quite a bit between different disorders and even between different guidelines for the same disorder. For example, guidelines differ on:

• How many medication trials are required before considering someone treatment resistant (ranging from 2-3 for depression)
• What medication doses and durations are considered adequate
• How to assess whether there has been enough symptom improvement

This inconsistency makes it difficult to compare results across studies and ensure patients are receiving appropriate care. The authors recommend developing more standardized definitions.

What causes treatment resistance?

There are several potential reasons why someone may not respond adequately to psychiatric treatments:

Pseudo-resistance

In some cases, what looks like treatment resistance may actually be “pseudo-resistance” - when a person appears not to be responding, but hasn’t truly received adequate treatment. This can happen due to:

• Misdiagnosis of the underlying condition
• Not taking medications as prescribed
• Problems with how the body processes the medication (e.g. too rapid metabolism)
• Use of other substances that interfere with the medication

Carefully assessing for these factors is important before concluding someone is truly treatment resistant.

Neurobiological differences

For those who are genuinely treatment resistant, there may be underlying differences in brain biology compared to those who respond well to standard treatments. Some possibilities researchers are investigating include:

• More severe underlying brain changes that standard medication doses can’t fully address
• Different neurotransmitter systems affected compared to typical cases
• Involvement of inflammatory processes in the brain
• Genetic factors affecting how medications are processed or how the brain responds

Better understanding these neurobiological mechanisms could help guide development of new, more targeted treatments.

What new approaches are being developed?

The paper highlights several new directions researchers and pharmaceutical companies are exploring for treatment-resistant psychiatric disorders:

New medications

Only a few medications are currently approved specifically for treatment-resistant conditions:

• Clozapine for treatment-resistant schizophrenia
• Esketamine (a form of ketamine) for treatment-resistant depression
• Combination of olanzapine and fluoxetine for treatment-resistant depression

However, a number of new drugs targeting different brain mechanisms are now in clinical trials, including for treatment-resistant schizophrenia, depression, bipolar disorder, and OCD.

Brain stimulation techniques

Non-medication approaches like transcranial magnetic stimulation, vagus nerve stimulation, and deep brain stimulation are being studied, particularly for depression and OCD that hasn’t responded to standard treatments.

Personalized medicine approaches

There’s increasing interest in using genetic testing or biomarkers to identify which treatments may work best for individual patients. This could help tailor treatment choices and potentially avoid multiple failed medication trials.

Targeting inflammation

Some studies have found higher levels of inflammation in the body and brain in subgroups of patients with treatment-resistant depression and schizophrenia. Clinical trials are now testing whether anti-inflammatory medications may help these patients.

What are the key challenges and future directions?

The authors identify several important issues that need to be addressed to make progress in understanding and treating resistant psychiatric illnesses:

1. Developing more consistent definitions and criteria for treatment resistance across disorders

2. Conducting more research to understand the underlying biology and identify potential biomarkers

3. Increasing overall research investment and drug development for treatment resistance, given how common and impactful it is

4. Considering resistance to specific symptom domains (e.g. negative symptoms in schizophrenia) rather than only overall illness

5. Taking a more personalized medicine approach to match patients with the most appropriate treatments earlier

6. Exploring treatments that work across diagnostic categories for common symptom domains like depression or psychosis

Conclusions

• Treatment resistance is very common in psychiatry but has been understudied relative to its impact.
• More consistent definitions and assessment approaches are needed across disorders.
• New treatments targeting different biological mechanisms show promise but require further research.
• A shift toward more personalized treatment approaches may help address resistant symptoms earlier and more effectively.