June 12, 2006

Treatment-Resistant Schizophrenia: Making the Determination

A summary of an article on "Treatment-resistent Schizophrenia" in Psychiatric Times May 2002

Some people suffering from schizophrenia never seem to get successful results from medications, and other therapeutic methods. These people are then deemed as having "treatment-resistant schizophrenia", but there's speculation that this is not the case for everyone with that label.

Many factors could influence a psychiatrist to believe someone has treatment-resistant schizophrenia and these should be looked into more thoroughly.

Some of these factors are:

• Medication noncompliance, even partial noncompliance.
• Variations in metabolic rates among individuals, influencing effectiveness of drug dosage.
• Inaccurate initial diagnosis (temporal-lobe epilepsy mimics schizophrenia)
• Lack of multiple medications (many people need several different meds to control for a range of symptoms)
• Adequately assessing success with treatment (how long did you try the medication, under what dosages)

This article attempts to relate proper protocol for certain treatment attempts when dealing with someone suspected of having treatment resistant schizophrenia.

Typical Antipsychotics

These drugs have been found to be very unsuccessful in attempting to treat someone considered "treatment-resistant". A 1998 article found that fewer than 5% of these patients responded to Haldol (haloperidol, a common typical antipsychotic). And in reviewing a 1994 paper, increasing dosage provided increased side effects without comparable increase in effectiveness.

This article states a good length in assessing typical antipsychotic effectiveness is about 6 weeks.

"As an example, little or no response to 20 mg/day of haloperidol after six to eight weeks should be considered a failure. An inadequate response should lead to trials of the atypical antipsychotics"

Atypical Antipsychotics (excluding clozapine)

There is no consistent evidence to conclude one atypical antipsychotic is far superior to another (clozapine is not included in this statement), or that inability to get successful results from one means the rest will also be unsuccessful. They so not appear to be interchangeable. But more research needs to be conducted to fully understand their differences.

"An adequate trial of an atypical antipsychotic should be at least eight to 12 weeks on a higher dose of the medication -- for example 12 mg/day of risperidone, 40 mg/day of olanzapine, 800 mg/day of quetiapine or 200 mg/day of ziprasidone."

This article recommends two trails, and that side effect prevalence should help determine which drugs to try first. Risperidone and Olanzapine seem to have the most promising research supporting their success rates.


Clozapine is considered to be the most successful in treating schizophrenia, but does require special monitoring for some dangerous side effects (a reason physician suggest trying other drugs first). Its main purpose is to treat those considered treatment-resistant.

Because clozapine's full effects take longer than previous meds, this article suggests a trail of 3 to 4 months, and note others believe it should be more like 6 months to 1 year.

"Typical clozapine doses range from 300 mg/day to 500 mg/day, and doses of up to 900 mg/day can be used. Some data suggest that minimum plasma levels between 350 ng/ml and 500 ng/ml are associated with increased therapeutic response (Kronig et al., 1995). A lack of noticeable response at two months may be better assessed with a clozapine blood level."

Augmentation Strategies and Results

Drug combinations are often used in cases where clozapine and not other treatments are successful. There isn't any consistant evidence on which combinations work best, or if they are really helpful at all. All evidence is support by case studies, which is very poor methodology in reflecting the efficacy of the entire population (meaning the results for one individual are not strong enough evidence that it will work for most people)

"We have seen many cases of patients with schizophrenia taking three different antipsychotics, several mood stabilizers, benzodiazepines and an antidepressant without any clear documentation of improvement -- a strategy we have termed irrational polypharmacy."

"A number of augmentation strategies have been proposed, which include the addition of lithium, an anticonvulsant, a second antipsychotic, a benzodiazepine or a course of electroconvulsive therapy (ECT). Psychosocial treatment may also be used as an augmentation strategy."

Based on the available research lithium has not been shown to produce successful results, and combined with clozapine increases severe side effect risks.

Inconsistent results have been found with anticonvulsant medications. Some studies found benefits in the beginning of treatment with anticonvulsants, but that the benefits decreased over time. Combing these drugs with clozapine may be helpful for reducing the risk of seizer. Divalproex is currently being prescribed and still underinvestigation, but shows the most promise for anticonvulsant medications treating schizophrenia.

Combining antipsychotic medications is a trail and error process, meaning no standard has been developed on which combinations work best, or which should be used to account for specific symptoms.

"Since some of the atypical antipsychotics such as clozapine and quetiapine have relatively weak dopamine (D2) antagonism, there may be some justification for adding a more potent D2 antagonist such as haloperidol, risperidone or olanzapine to augment an inadequate response."

ECT (electro convulsive therapy) has evidence supporting its effectiveness in treating those resistant to other methods. But there can be risks, memory loss, and of course many people aren’t willing to participate.

Psychotherapy is another method which needs more research, but has evidence to support its implementation accompanied by medications. This treatment option is great because it's risk level is very low, but requires commitment, so compliance rates might not that high.


Physicians need to adequately assess a patient before deeming them resistant to treatment. There are many different treatments to consider, and they differ on how long one should wait before deciding it's not effective. Combining many medications and utilizing large dosages may be more harmful than helpful. Psychotherapy is always a safe option to add to medication treatment, and has shown success (mainly CBT, psychoeducation, family involvement).

But there is a select group of individuals who will never get a "favorable" outcome based on our current understanding of how to treat the disorder. The only option is then to settle for the best results possible, and push further research on developing new treatment methods.

Full Article:
Treatment-Resistant Schizophrenia: Making the Determination Psychiatric Times (www.psychiatrictimes.com)May 2002 Vol. XIX Issue 5.

Related Stories:

Adjunctive Topiramate for Treatment Resistant Schizophrenia


I like researching. I am a psychology student currently. I liked your articles on Schizophrenia

Posted by: Ranjeeta Nair at April 10, 2007 07:35 AM

I am a student at a medical college. i need criteria to diagnose treatment resistant schizophrenia.

Posted by: dr amal ch baishya at June 29, 2007 03:09 AM

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