How to Identify and Manage Treatment-Resistant Schizophrenia

When a schizophrenic patient fails to respond to at least two trials of antipsychotic medications, their specific form of schizophrenia is then classified as a case of treatment-resistant schizophrenia (TRS). Beyond that, there are many other factors to consider when identifying and managing Treatment-Resistant Schizophrenia that we will discuss below, and we will begin to understand the role of pharmacogenetics in these cases.

Is it Treatment-Resistant Schizophrenia?

Patients with treatment resistant schizophrenia should be reevaluated 12 weeks after their first episode of psychosis (after two antipsychotic trials of at least 6 weeks duration at an adequate dose), according to consensus treatment guidelines.

Clozapine is the only antipsychotic drug that doesn’t fall into this definition. Mainly, because it’s almost never prescribed as first-line treatment and partly because it’s actually the drug of choice for treatment resistant schizophrenia when all else fails.

Treatment-Resistant Schizophrenia cases that fail to respond to Clozapine are subcategorized into Clozapine-resistant and likewise, cases that don’t respond to Electroconvulsive therapy are labeled ECT-resistant. There might be other reasons that a schizophrenic patient is not responding to his meds other than treatment resistant schizophrenia. Here are some questions to ask to know if it’s a treatment resistant schizophrenia case or not:

Is it really schizophrenia?
A lack of response to treatment can suggest that it’s actually something else. Common disorders that often get falsely labeled as schizophrenia are: mania, depression with psychotic features, brain tumors, and encephalopathies.

Is the patient adhering to his medication?
More than half of the patients do not take their medicine as prescribed and non-compliance is a primary cause of non-response.

Were sufficient plasma levels achieved?
When in doubt if the patient is complying with his meds or not, some physicians consider running plasma levels of the drug. However, no clear relationship between the drug concentration in the plasma and its response has been established yet in treatment resistant schizophrenia. Still, it could provide some insight.

Are the drug’s side effects hiding his improvement?
Antipsychotic side effects can conceal therapeutic responses. For example, akathisia which is motor restlessness might be mistaken for agitation, and parkinsonism can be mistaken for schizophrenia negative symptoms.

It’s TRS. What’s next?

There is more than one way to deal with Treatment-Resistant Schizophrenia. While clozapine is the drug of choice when all else fails, it still counts as a safety net that physicians hope to not use due to its serious side effects. Some other strategies, while not always recommended, are often used clinically including:

Dose increase – Obviously, using higher doses than approved is not recommended However, patients with certain genetic factors that lead to rapid metabolism of the drug can benefit from a dose increase. This is especially true when their plasma level of the drug is below the therapeutic range.

Combination strategies – This means using two drugs of the same group, meaning we use two different types of antipsychotics. This is commonly used in clinical practice despite research finding small effects of this strategy.

Augmentation strategies – means using two drugs of different groups, like using an antipsychotic with an antidepressant. However, this method increases the side effects and puts the patient at risk of drug interactions. Augmentation strategies are often preserved when it’s targeting a specific symptom of schizophrenia-like using Benzodiazepines to sedate an agitated patient or using antidepressants to treat schizophrenia’s negative symptoms.

Switching to Clozapine - Clozapine is the only evidence-based therapy for treatment resistant schizophrenia, with a response rate of 60–70% of individuals treated. Clozapine, on the other hand, does not work for all treatment resistant schizophrenia sufferers.

What Role Does Pharmacogenetics Play?

Pharmacogenetics studies how genes impact drug pharmacokinetics and pharmacodynamics, as well as how a single gene or a group of genes might influence a patient's pharmaceutical response. Identifying particular genetic variants that indicate a good response to clozapine or low risk of side events is one approach to apply pharmacogenetics in treatment resistant schizophrenia.

The genetics of the dopaminergic system
Researchers point out that the dopaminergic system is involved in clozapine response mediation. Clozapine effectiveness has also been linked to dopamine receptor type 2 and type 1 genetic variation, as well as dopamine transporter haplotypes.

The genetics of the serotonergic system
Clozapine reaction is not predicted by one single polymorphism. As a result, researchers have attempted to predict therapy response by combining polymorphisms in many genes. One test included six distinct genetic variants in neurotransmitter receptor-related genes and predicted clozapine responsiveness with a 77 percent accuracy.

Metabolism of Clozapine
Clozapine metabolism is largely controlled by the CYP1A2 enzyme. The discovery of numerous functional variations in CYP1A2 with well-defined effects on clozapine metabolism supports genetic investigations of clozapine drug response.

Clozapine and Agranulocytosis
Fears about clozapine-induced agranulocytosis scare both patients and physicians away from using Clozapine. There is some indication that genetic variation increases vulnerability to clozapine induced agranulocytosis and therefore it can be predicted and prevented in susceptible patients.

Clozapine and metabolic issues
- There is a reliably replicated genetic variation for clozapine-associated weight gain.

- Polymorphisms in genes that encode a protein that facilitates feedback regulation of lipid metabolism have been linked to metabolic syndrome associated with clozapine usage.

Challenges in applying pharmacogenomics in treatment resistant schizophrenia

Schizophrenia is an heterogeneous illness with a wide range of clinical manifestations.

Changing environmental and clinical variables which influence clozapine responsiveness and tolerance, challenges pharmacogenomic research even more.

Implementation will need physician education, the inclusion of pharmacogenomic testing recommendations into treatment resistant schizophrenia clinical guidelines, and the use of integrated medical records.

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When it comes to Treatment Resistant Schizophrenia there are certain questions that you should be asking when it comes to identifying and managing symptoms on a case by case basis.

If you or someone you know is struggling psychologically or with treatment resistant schizophrenia, please call us at 844-543-3242 to confidentially hear about the options available to you from one of our Care Guides.

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