Cases That Test Your Skills

Can a wakefulness-promoting agent augment schizophrenia treatment?

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Schizophrenia has plagued Mr. X for most of his adult life. He finally responds to a novel antipsychotic after many failed trials, but severe negative symptoms and medication-associated sedation are stalling his progress. In their efforts to reintegrate the patient, these doctors pose the question:



History: A long, losing battle

Mr. X, 41, has had schizophrenia, paranoid type, since age 24. Unable to work, keep house, or even groom himself, he has lived his entire life with his mother, his principal advocate and caretaker. He has been hospitalized 11 times for persecutory delusions, most recently 2 years ago at our medical center..

Numerous antipsychotics, including risperidone, haloperidol, quetiapine, clozapine, and thiothixene, did not work. He has responded best to olanzapine, but some mild paranoid symptoms and significant negative symptoms (alogia, anhedonia, amotivation, hypersomnia, restricted affect) persist.

He gained 30 pounds within 6 months after starting olanzapine. He was keeping his weight at 230 pounds and his body mass index (BMI) at 31.3. (A normal BMI is <25; a BMI >30 is considered obese.)

The patient was maintained on olanzapine 20 mg/d, but higher dosages caused oversedation. At the hospital, he would sleep through breakfast, get up late in the morning, then lie around until bedtime.

As an outpatient, he had no social contact outside the home. While hospitalized, Mr. X attended a therapy group on his ward, but never participated in the discussion. His speech was profoundly deficient; he never volunteered information and never responded to questions with anything more than a barely audible “yes” or “ no ”

How would you help Mr. X? Would you augment the olanzapine therapy or consider another antipsychotic, even one that failed the first time? Which negative symptom would you address first?

Drs. Yu’s and Maguire’s observations

Compared with the older antipsychotic agents, specifically haloperidol and thiothixene in this case, the newer antipsychotics (clozapine, risperidone, olanzapine, quetiapine, and ziprasidone) have demonstrated the ability to comprehensively treat schizophrenia.1-4 But these novel agents sometimes fail to remedy the negative symptoms. Thus, as is the case with Mr. X, many patients with schizophrenia whose positive symptoms are controlled realize little or no improvement in quality of life.

Olanzapine and risperidone have more effectively reduced the negative symptoms of schizophrenia than have the older antipsychotics,1-4 but—as we see with Mr. X—their record in treating negative symptoms is far from perfect. Additionally, sedation secondary to the antipsychotic may worsen the negative symptoms.

What’s more, the newer agents are associated with potential weight gain.5-7 Mr. X’s weight will need to be addressed, but with much caution. Many agents prescribed for weight loss, notably amphetamines, are avoided in psychotic patients because of the potential for abuse and worsening psychosis.8

Augmentation with modafinil, a wakefulness-promoting agent, is being considered for Mr. X. Although modafinil’s efficacy against obesity has not specifically been tested, studies have shown that this agent, which has actions similar to those of sympathomimetic agents, offers a lower abuse potential. Gold and Balster found that the medication was 250 times less potent than amphetamine and 15 times less potent than ephedrine in producing cocaine-like discriminative stimulus effects in rats.9 Single oral doses of modafinil did not cause elation or euphoria in healthy volunteers or those with substance abuse disorders.10,11 And compared with amphetamines, modafinil has a limited side-effect profile, with weak peripheral sympathomimetic activity and minimal effects on hemodynamics.12

Though it is best to minimize both the number of medications and the dosage for each patient, augmentation is still needed in some cases.13-15

Treatment augmentation: An agent is added

Mr. X’s olanzapine was increased to 30 mg/d. Modafinil, 100 mg/d, was then added to reduce the sedation associated with the higher olanzapine dosage.

Within a week, Mr. X’s negative symptoms had begun to improve. He started to speak more often and more clearly; his previously monotone voice exhibited a small degree of intonation and inflection. His fatigue decreased, and he was able to stay awake through breakfast and throughout the day.

That first week, he exhibited a brightened affect and more energy. He began to socialize to some extent with other patients in the hospital therapy group and was less isolated than before.

This slight but sudden improvement encouraged us. While he still showed slight paranoid ideations, he looked forward to a safe discharge and returning home to his family.

At this point, would you increase the dosage of either modafinil or olanzapine, or stay the course and monitor the patient’s improvement?

Drs. Yu’s and Maguire’s observations

Modafinil is a novel compound indicated for narcolepsy treatment. Though its precise mechanism is unknown, modafinil is neither a direct- nor indirect-acting dopamine receptor agonist and is inactive in several in vivo preclinical models capable of detecting enhanced dopaminergic activity.16 Therefore, the agent’s pharmacologic profile may be favorable for off-label use in treating negative symptoms of schizophrenia. Modafinil also has been shown to be effective as an augmentation therapy in depression, especially with treating fatigue symptoms.17


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