Why is loxapine overlooked, underprescribed for psychosis?


I have always tried to practice common sense psychiatry, however, sometimes it seems I am alone in this pursuit. My best example is the minimal prescribing of loxapine (Adasuve) for treating the problem of psychosis, most notably schizophrenia.

Dr. Carl C. Bell, staff psychiatrist at Jackson Park Hospital’s surgical-medical/psychiatric inpatient unit, and clinical professor emeritus, department of psychiatry, University of Illinois at Chicago

Dr. Carl C. Bell

Mind you, neither I nor anyone in family own stock in any pharmaceutical companies. I don’t lecture for them, so I have no conflicts in writing about this observation – which I hope will improve patient care, thereby saving lives and making a difference.

Everyone should be familiar with the evolution of atypical antipsychotics and how these medications are touted as “second-generation” classes of medication advertised as superior to the older, first-generation antipsychotics. However, as we get more experience with the second-generation atypical antipsychotics, we are learning that they have problematic side effects of their own. For example, they are associated with metabolic syndrome, so they cause weight gain, hyperglycemia, increased risk of stroke, sudden cardiac death, blood clots, and diabetes. Maybe these problems are so endemic in the low-income, African American population I treat that I am overly sensitive to trying to prevent these medical disorders while treating a patient’s mental illness. However, my public health leanings have long caused me to think that low-income African Americans are the canary in America’s health status coal mine, as it seems that what hits this group first eventually will hit the majority population. Accordingly, it seems to me that it is well advised to pay attention to this group’s well-being, physical health, and mental health challenges.

Everyone also should be aware that clozapine (Clozaril) had been dubbed the first atypical antipsychotic. But, in some regard, that designation might be given to thioridazine – although some maintain that the ratio of serotonergic to dopamine effects is not strong enough to earn that title. Unfortunately, both thioridazine and clozapine have serious side effects. Thioridazine is associated with severe cardiac arrhythmias, and clozapine has been associated with the aforementioned side effects of atypical antipsychotics but also can cause life-threatening agranulocytosis, necessitating regular white blood cell counts to monitor for this possibility.

What not everyone knows is that loxapine is a member of the dibenzoxazepine class of medication, and it is structurally related to clozapine, which belongs class of medication known as dibenzodiazepines – a class that is extraordinarily similar to dibenzoxazepine. The late William Glazer, MD, a distinguished psychopharmacologist long affiliated with Yale University, New Haven, Conn., even suggested that loxapine might behave as an atypical antipsychotic (J Clin Psychiatry. 1999;60 Suppl 10:42-6). Extensive clinical experience with loxapine suggests the same but with some key differences from the standard atypical antipsychotics regarding its side-effect profile.

First, loxapine, despite being chemically related to clozapine, does not cause agranulocytosis, so the need for white blood cell monitoring is not necessary. Second, I have not seen the problematic metabolic syndrome caused by standard atypical antipsychotic medication. It amazes me when I see patients on aripiprazole, clozapine, olanzapine, quetiapine, risperidone, or ziprasidone who also have diabetes and are on metformin – especially when the development of the patients’ diabetes can be traced back to when they were put on an atypical antipsychotic. I often find myself taking patients off their atypical antipsychotic and putting them on loxapine, resulting in gradual weight loss while maintaining the patients’ stable mental status and absence of psychotic symptoms.

It seems to me that if clozapine and loxapine are so similar (they both bind to serotonin and dopamine receptors), loxapine should be the first drug of choice for the treatment of psychotic symptoms. It acts like an atypical but without the problems of weight gain, hyperglycemia, increased risk of stroke, sudden cardiac death, blood clots, and diabetes that the atypicals may cause. Most of the hundreds of patients with psychotic symptoms I have treated over the past 40 years are on the low dose of loxapine 25 mg at bedtime (although the prescribing information on loxapine says it has to be given at least twice a day, as the half life of the medication is only 4 hours). In some rare instances, I prescribe a total of 50 mg at bedtime.

So, not prescribing loxapine does not make sense to me – other than the medication is generic and so it is not being marketed aggressively by people who make money from prescribing medication and are practicing money, not medicine. The other possibility is that most psychiatrists might not know the connection between clozapine and loxapine, so I thought I should use my influence (what little I have) to inform.

Dr. Bell is staff psychiatrist at Jackson Park Hospital’s surgical-medical/psychiatric inpatient unit in Chicago; and chairman of the department of psychiatry at Windsor University, St. Kitts. He also is clinical professor emeritus, department of psychiatry, University of Illinois at Chicago; former president/CEO of Community Mental Health Council; and former director of the Institute for Juvenile Research (the birthplace of child psychiatry), all in Chicago.

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